sGC STIMULATORS

ABSTRACT

Compounds of Formula I are described. They are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds may be useful for treating, preventing or managing various disorders that are herein disclosed.

This patent application claims the benefit of U.S. ProvisionalApplication No. 61/702,303 filed 18 Sep. 2012, the disclosures of whichare herein incorporated by reference.

FIELD OF THE INVENTION

The present disclosure relates to stimulators of soluble guanylatecyclase (sGC), pharmaceutical formulations comprising thereof and theiruses, alone or in combination with one or more additional agents, fortreating and/or preventing various diseases, wherein an increase in theconcentration of nitric oxide (NO) or an increase in the concentrationof cyclic Guanosine Monophosphate (cGMP) might be desirable.

BACKGROUND OF THE INVENTION

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide(NO) in vivo. sGC can be activated via both NO-dependent andNO-independent mechanisms. In response to this activation, sGC convertsGTP into the secondary messenger cyclic GMP (cGMP). The increased levelof cGMP, in turn, modulates the activity of downstream effectorsincluding protein kinases, phosphodiesterases (PDEs) and ion channels.

In the body, NO is synthesized from arginine and oxygen by variousnitric oxide synthase (NOS) enzymes and by sequential reduction ofinorganic nitrate. Three distinct isoforms of NOS have been identified:inducible NOS (iNOS or NOS II) found in activated macrophage cells;constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmissionand long term potentiation; and constitutive endothelial NOS (eNOS orNOS III) which regulates smooth muscle relaxation and blood pressure.

Experimental and clinical evidence indicates that reducedbioavailability and/or responsiveness to endogenously produced NOcontributes to the development of cardiovascular, endothelial, renal andhepatic disease, as well as erectile dysfunction and other sexualdisorders (e.g. female sexual disorder or vaginal atrophy). Inparticular, the NO signaling pathway is altered in cardiovasculardiseases, including, for instance, systemic and pulmonary hypertension,heart failure, angina, stroke, thrombosis and other thromboembolicdiseases, peripheral arterial disease, fibrosis of the liver, lung orkidney and atherosclerosis.

sGC stimulators are also useful in the treatment of lipid relateddisorders such as e.g., dyslipidemia, hypercholesterolemia,hypertriglyceridemia, sitosterolemia, fatty liver disease, andhepatitis.

Pulmonary hypertension (PH) is a disease characterized by sustainedelevation of blood pressure in the pulmonary vasculature (pulmonaryartery, pulmonary vein and pulmonary capillaries), which results inright heart hypertrophy, eventually leading to right heart failure anddeath. In PH, the bioactivity of NO and other vasodilators such asprostacyclin is reduced, whereas the production of endogenousvasoconstrictors such as endothelin is increased, resulting in excessivepulmonary vasoconstriction. sGC stimulators have been used to treat PHbecause they promote smooth muscle relaxation, which leads tovasodilation.

Treatment with NO-independent sGC stimulators also promoted smoothmuscle relaxation in the corpus cavernosum of healthy rabbits, rats andhumans, causing penile erection, indicating that sGC stimulators areuseful for treating erectile dysfunction.

NO-independent, heme-dependent, sGC stimulators, such as those disclosedherein, have several important differentiating characteristics,including crucial dependency on the presence of the reduced prostheticheme moiety for their activity, strong synergistic enzyme activationwhen combined with NO and stimulation of the synthesis of cGMP by directstimulation of sGC, independent of NO. The benzylindazole compound YC-1was the first sGC stimulator to be identified. Additional sGCstimulators with improved potency and specificity for sGC have sincebeen developed. These compounds have been shown to produceanti-aggregatory, anti-proliferative and vasodilatory effects.

Since compounds that stimulate sGC in an NO-independent manner offerconsiderable advantages over other current alternative therapies, thereis a need to develop novel stimulators of sGC. They are potentiallyuseful in the prevention, management and treatment of disorders such aspulmonary hypertension, arterial hypertension, heart failure,atherosclerosis, inflammation, thrombosis, renal fibrosis and failure,liver cirrhosis, lung fibrosis, erectile dysfunction, female sexualarousal disorder and vaginal atrophy and other cardiovascular disorders;they are also potentially useful for the prevention, management andtreatment of lipid related disorders.

SUMMARY OF THE INVENTION

The present invention is directed to compounds according to Formula I,or pharmaceutically acceptable salts thereof,

wherein:

-   ring B is a 5-membered heteroaryl ring selected from furan or    thiophene;-   n is an integer selected from 0 to 3;-   each J^(B) is independently selected from halogen, —CN, a C₁₋₆    aliphatic, —OR^(B) or a C₃₋₈ cycloaliphatic group; wherein each said    C₁₋₆ aliphatic and each said C₃₋₈ cycloaliphatic group is optionally    and independently substituted with up to 3 instances of R³;-   each R^(B) is independently selected from hydrogen, a C₁₋₆ aliphatic    or a C₃₋₈ cycloaliphatic ring; wherein each said C₁₋₆ aliphatic and    each said C₃₋₈ cycloaliphatic ring is optionally and independently    substituted with up to 3 instances of R^(3a);-   each R³ is independently selected from halogen, —CN, C₁₋₄ alkyl,    C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);-   each R^(3a) is independently selected from halogen, —CN, C₁₋₄ alkyl,    C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);-   X is selected from N, C-J^(D) or C—H;-   o is an integer selected from 0 to 3;-   each J^(D) is independently selected from halogen, —NO₂, —OR^(D),    —SR^(D), —C(O)R^(D), —C(O)OR^(D), —C(O)N(R^(D))₂, —CN, —N(R^(D))₂,    —N(R^(d))C(O)R^(D), —N(R^(d))C(O)OR^(D), —SO₂R^(D), —SO₂N(R^(D))₂,    —N(R^(d))SO₂R^(D), a C₁₋₆ aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈    cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to 8-membered    heterocyclic ring or a 5 to 10-membered heteroaryl ring; wherein    each said 4 to 8-membered heterocylic ring and each said 5 to    10-membered heteroaryl ring contains between 1 and 3 heteroatoms    independently selected from O, N or S; and wherein each said C₁₋₆    aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 6 to    10-membered aryl ring, each said 4 to 8-membered heterocyclic ring    and each said 5 to 10-membered heteroaryl ring is optionally and    independently substituted with up to 3 instances of R⁵;-   each R^(D) is independently selected from hydrogen, a C₁₋₆    aliphatic, —(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4    to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered    heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring    and each said 5 to 6-membered heteroaryl ring contains between 1 and    3 heteroatoms independently selected from O, N or S; and wherein    each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring, each    said 4 to 8-membered heterocyclic ring, each said phenyl and each    said 5 to 6-membered heteroaryl ring is optionally and independently    substituted with up to 3 instances of R^(5a);-   each R^(d) is independently selected from hydrogen, a C₁₋₆    aliphatic, —(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4    to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered    heteroaryl ring; wherein each said heterocylic ring and each said    heteroaryl ring contains between 1 and 3 heteroatoms independently    selected from O, N or S; and wherein each said C₁₋₆ aliphatic, each    said C₃₋₈ cycloaliphatic ring, each said 4 to 8-membered    heterocyclic ring, each said phenyl and each said 5 to 6-membered    heteroaryl ring is optionally and independently substituted by up to    3 instances of R^(5b);-   each R^(f) is independently selected from a C₃₋₈ cycloaliphatic    ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to    6-membered heteroaryl ring; wherein each said heterocylic ring and    each said heteroaryl ring contains between 1 and 3 heteroatoms    independently selected from O, N or S; and wherein each said C₁₋₆    aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 4 to    8-membered heterocyclic ring, each said phenyl and each said 5 to    6-membered heteroaryl ring is optionally and independently    substituted by up to 3 instances of R^(5c);-   when J^(D) is —C(O)N(R^(D))₂, —N(R^(D))₂ or —SO₂N(R^(D))₂, the two    instances of R^(D) together with the nitrogen atom attached to the    R^(D), alternatively form a 4 to 8-membered heterocyclic ring or a    5-membered heteroaryl ring; wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring    optionally contains up to 2 additional heteroatoms independently    selected from N, O or S, and wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring is    optionally and independently substituted by up to 3 instances of R⁵;    or-   when J^(D) is —N(R^(d))C(O)R^(D), the R^(D) group together with the    carbon atom attached to the R^(D) group, with the nitrogen atom    attached to the R^(d) group and with the R^(d) group alternatively    form a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl    ring; wherein each said 4 to 8-membered heterocyclic ring and each    said 5-membered heteroaryl ring optionally contains up to 2    additional heteroatoms independently selected from N, O or S, and    wherein each said 4 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring is optionally and independently    substituted by up to 3 instances of R⁵;-   when J^(D) is —N(R^(d))C(O)OR^(D), the R^(D) group together with the    oxygen atom attached to the R^(D) group, with the carbon atom of the    —C(O)— portion of the —N(R^(d))C(O)OR^(D) group, with the nitrogen    atom attached to the R^(d) group, and with the R^(d) group    alternatively form a 4 to 8-membered heterocyclic ring or a    5-membered heteroaryl ring; wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring    optionally contains up to 2 additional heteroatoms independently    selected from N, O or S, and wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring is    optionally and independently substituted by up to 3 instances of R⁵;-   when J^(D) is —N(R^(d))SO₂R^(D), the R^(D) group together with the    oxygen atom attached to the R^(D) group, with the sulfur atom    attached to said oxygen atom in the —SO₂R^(D) portion of the    N(R^(d))SO₂R^(D) group, with the nitrogen atom attached to the R^(d)    group, and with the R^(d) group alternatively form a 4 to 8-membered    heterocyclic ring or a 5-membered heteroaryl ring; wherein each said    4 to 8-membered heterocyclic ring and each said 5-membered    heteroaryl ring optionally contains up to 2 additional heteroatoms    independently selected from N, O or S, and wherein each said 4 to    8-membered heterocyclic ring and each said 5-membered heteroaryl    ring is optionally and independently substituted by up to 3    instances of R⁵;-   each R⁵ is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(5a) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(5b) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(5c) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R⁶ is independently selected from hydrogen, a C₁₋₄ alkyl, a    C₂₋₄ alkenyl, phenyl, a C₇₋₁₂ aralkyl or a C₃₋₈ cycloalkyl ring;    wherein each said C₁₋₄ alkyl, each said C₂₋₄ alkenyl, each said    phenyl, each said C₇₋₁₂ aralkyl and each said C₃₋₈ cycloalkyl group    is optionally and independently substituted with up to 3 instances    of halogen;-   alternatively, two instances of R⁶ linked to the same nitrogen atom    of R⁵, together with said nitrogen atom of R⁵, form a 5 to    8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 5 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S; or-   alternatively, one instance of R⁶ linked to a nitrogen atom of R⁵    and one instance of R⁶ linked to a carbon or sulfur atom of the same    R⁵, together with said nitrogen and said carbon or sulfur atom of    the same R⁵, form a 5 to 8-membered heterocyclic ring or a    5-membered heteroaryl ring; wherein each said 5 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring    optionally contains up to 2 additional heteroatoms independently    selected from N, O or S;-   or, alternatively, two J^(D) groups attached to two vicinal ring D    atoms, taken together with said two vicinal ring D atoms, form a 5    to 7-membered heterocycle resulting in a fused ring D wherein said 5    to 7-membered heterocycle contains from 1 to 3 heteroatoms    independently selected from N, O or S; and wherein said 5 to    7-membered heterocycle is optionally and independently substituted    by up to 3 instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄    alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl), —O(C₁₋₄    haloalkyl), oxo or phenyl; wherein said phenyl is optionally and    independently substituted by up to three instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);-   R^(C) is a ring C; ring C is a phenyl ring, a monocyclic 5 or    6-membered heteroaryl ring, a bicyclic 8 to 10-membered heteroaryl    ring, a monocyclic 3 to 10-membered cycloaliphatic ring, or a    monocyclic 4 to 10-membered heterocycle; wherein said monocyclic 5    or 6-membered heteroaryl ring, said bicyclic 8 to 10-membered    heteroaryl ring, or said monocyclic 4 to 10-membered heterocycle    contain between 1 and 4 heteroatoms selected from N, O or S; wherein    said monocyclic 5 or 6-membered heteroaryl ring is not a    1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5 to    6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl    ring, or monocyclic 4 to 10-membered heterocycle is optionally and    independently substituted with up to 3 instances of J^(C);-   each J^(C) is independently selected from halogen, —CN, —NO₂, a C₁₋₆    aliphatic, —OR^(H), —SR^(H), —N(R^(H))₂, a C₃₋₈ cycloaliphatic ring    or a 4 to 8-membered heterocyclic ring; wherein said 4 to 8-membered    heterocyclic ring contains 1 or 2 heteroatoms independently selected    from N, O or S; wherein each said C₁₋₆ aliphatic, each said C₃₋₈    cycloaliphatic ring and each said 4 to 8-membered heterocyclic ring,    is optionally and independently substituted with up to 3 instances    of R⁷; or alternatively, two J^(C) groups attached to two vicinal    ring C atoms, taken together with said two vicinal ring C atoms,    form a 5 to 7-membered heterocycle resulting in a fused ring C;    wherein said 5 to 7-membered heterocycle contains from 1 to 2    heteroatoms independently selected from N, O or S;-   each R^(H) is independently selected from hydrogen, a C₁₋₆    aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to 8-membered    heterocyclic ring; wherein each said 4 to 8-membered heterocylic    ring contains between 1 and 3 heteroatoms independently selected    from O, N or S; and wherein each said C₁₋₆ aliphatic, each said C₃₋₈    cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, is    optionally and independently substituted with up to 3 instances of    R^(7a);-   alternatively, two instances of R^(H) linked to the same nitrogen    atom of J^(C), together with said nitrogen atom of J^(C), form a 4    to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 4 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S, and wherein each    said 4 to 8-membered heterocyclic ring and each said 5-membered    heteroaryl ring is optionally and independently substituted by up to    3 instances of R^(7b); or-   each R⁷ is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or    an oxo group; wherein each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(7a) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or    an oxo group; wherein each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(7b) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or    an oxo group; wherein each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R⁸ is independently selected from hydrogen, a C₁₋₄ alkyl, C₁₋₄    haloalkyl or a C₃₋₈ cycloalkyl ring; wherein each said cycloalkyl    group is optionally and independently substituted with up to 3    instances of halogen;-   alternatively, two instances of R⁸ linked to the same nitrogen atom    of R⁷, together with said nitrogen atom of R⁷, form a 5 to    8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 5 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S; and-   R^(A) is selected from hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄    haloalkyl.

The invention also provides a method of treating or preventing adisease, health condition or disorder in a subject in need thereof,comprising administering, alone or in combination therapy, atherapeutically or prophylactically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt thereof to the subject;wherein the disease, health condition or disorder is a peripheral,pulmonary, hepatic, liver, cardiac or cerebral vascular/endothelialdisorder or condition, a urogenital-gynecological disorder or condition,a thromboembolic disease, a fibrotic disorder, or other pulmonary orrespiratory disorder, renal or hepatic disorder, metabolic disorder,atherosclerosis or a lipid related disorder that benefits from sGCstimulation or from an increase in the concentration of NO or cGMP.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulae. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments.Rather, the invention is intended to cover all alternatives,modifications and equivalents that may be included within the scope ofthe present invention as defined by the claims. The present invention isnot limited to the methods and materials described herein but includeany methods and materials similar or equivalent to those describedherein that could be used in the practice of the present invention. Inthe event that one or more of the incorporated literature references,patents or similar materials differ from or contradict this application,including but not limited to defined terms, term usage, describedtechniques or the like, this application controls.

DEFINITIONS AND GENERAL TERMINOLOGY

For purposes of this disclosure, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version, and theHandbook of Chemistry and Physics, 75^(th) Ed. 1994. Additionally,general principles of organic chemistry are described in “OrganicChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999,and “March's Advanced Organic Chemistry”, 5^(th) Ed., Smith, M. B. andMarch, J., eds. John Wiley & Sons, New York: 2001, which are hereinincorporated by reference in their entirety.

As described herein, compounds of Formula I may be optionallysubstituted with one or more substituents, such as illustrated generallybelow, or as exemplified by particular classes, subclasses and speciesof the invention. The phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted.” Ingeneral, the term “substituted” refers to the replacement of one or morehydrogen radicals in a given structure with the radical of a specifiedsubstituent. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of the group. Whenmore than one position in a given structure can be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at each position unless otherwisespecified. As will be apparent to one of ordinary skill in the art,groups such as —H, halogen, —NO₂, —CN, —OH, —NH₂ or —OCF₃ would not besubstitutable groups.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, or 3. As described herein, aspecified number range of atoms includes any integer therein. Forexample, a group having from 1-4 atoms could have 1, 2, 3 or 4 atoms.When any variable occurs more than one time at any position, itsdefinition on each occurrence is independent from every otheroccurrence.

Selection of substituents and combinations envisioned by this disclosureare only those that result in the formation of stable or chemicallyfeasible compounds. Such choices and combinations will be apparent tothose of ordinary skill in the art and may be determined without undueexperimentation. The term “stable”, as used herein, refers to compoundsthat are not substantially altered when subjected to conditions to allowfor their production, detection, and, in some embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound is one that isnot substantially altered when kept at a temperature of 25° C. or less,in the absence of moisture or other chemically reactive conditions, forat least a week. A chemically feasible compound is a compound that canbe prepared by a person skilled in the art based on the disclosuresherein supplemented, if necessary, relevant knowledge of the art.

A compound, such as the compounds of Formula I or other compounds hereindisclosed, may be present in its free form (e.g. an amorphous form, or acrystalline form or a polymorph). Under certain conditions, compoundsmay also form co-forms. As used herein, the term co-form is synonymouswith the term multi-component crystalline form. When one of thecomponents in the co-form has clearly transferred a proton to the othercomponent, the resulting co-form is referred to as a “salt”. Theformation of a salt is determined by how large the difference is in thepKas between the partners that form the mixture.

Unless only one of the isomers is drawn or named specifically,structures depicted herein are also meant to include all stereoisomeric(e.g., enantiomeric, diastereomeric, atropoisomeric and cis-transisomeric) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Ra and Sa configurations foreach asymmetric axis, (Z) and (E) double bond configurations, and cisand trans conformational isomers. Therefore, single stereochemicalisomers as well as racemates, and mixtures of enantiomers,diastereomers, and cis-trans isomers (double bond or conformational) ofthe present compounds are within the scope of the present disclosure.Unless otherwise stated, all tautomeric forms of the compounds of thepresent disclosure are also within the scope of the invention.

The present disclosure also embraces isotopically-labeled compoundswhich are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. All isotopes of any particular atom or element as specified arecontemplated within the scope of the compounds of the invention, andtheir uses. Exemplary isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and¹²⁵I, respectively. Certain isotopically-labeled compounds of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (i.e.,³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms. In other embodiments, aliphatic groups contain 1-4aliphatic carbon atoms and in yet other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms. Suitable aliphatic groups include,but are not limited to, linear or branched, substituted or unsubstitutedalkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groupsinclude, but are not limited to: methyl, ethyl, propyl, butyl,isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propargyl,acetylene and the like.

The term “alkyl”, as used herein, refers to a saturated linear orbranched-chain monovalent hydrocarbon radical. Unless otherwisespecified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbonatoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbonatoms or 1-3 carbon atoms). Examples of alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon, sp² double bond, wherein the alkenyl radical includesradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations. Unless otherwise specified, an alkenyl groupcontains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms,2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbonatoms). Examples include, but are not limited to, vinyl, allyl and thelike.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon sptriple bond. Unless otherwise specified, an alkynyl group contains 2-20carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbonatoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examplesinclude, but are not limited to, ethynyl, propynyl, and the like.

The term “carbocyclic” refers to a ring system formed only by carbon andhydrogen atoms. Unless otherwise specified, throughout this disclosure,carbocycle is used as a synonym of “non-aromatic carbocycle” or“cycloaliphatic”. In some instances the term can be used in the phrase“aromatic carbocycle”, and in this case it refers to an “aryl group” asdefined below.

The term “cycloaliphatic” (or “non-aromatic carbocycle”, “non-aromaticcarbocyclyl”, “non-aromatic carbocyclic”) refers to a cyclic hydrocarbonthat is completely saturated or that contains one or more units ofunsaturation but which is not aromatic, and which has a single point ofattachment to the rest of the molecule. Unless otherwise specified, acycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused,spiro or bridged. In one embodiment, the term “cycloaliphatic” refers toa monocyclic C₃-C₁₂ hydrocarbon or a bicyclic C₇-C₁₂ hydrocarbon. Insome embodiments, any individual ring in a bicyclic or tricyclic ringsystem has 3-7 members. Suitable cycloaliphatic groups include, but arenot limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples ofaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl,cyclododecyl, and the like.

The term “cycloaliphatic” also includes polycyclic ring systems in whichthe non-aromatic carbocyclic ring can be “fused” to one or more aromaticor non-aromatic carbocyclic or heterocyclic rings or combinationsthereof, as long as the radical or point of attachment is on thenon-aromatic carbocyclic ring.

“Heterocycle” (or “heterocyclyl” or “heterocyclic), as used herein,refers to a ring system in which one or more ring members are anindependently selected heteroatom, which is completely saturated or thatcontains one or more units of unsaturation but which is not aromatic,and which has a single point of attachment to the rest of the molecule.Unless otherwise specified, through this disclosure, heterocycle is usedas a synonym of “non-aromatic heterocycle”. In some instances the termcan be used in the phrase “aromatic heterocycle”, and in this case itrefers to a “heteroaryl group” as defined below. The term heterocyclealso includes fused, spiro or bridged heterocyclic ring systems. Unlessotherwise specified, a heterocycle may be monocyclic, bicyclic ortricyclic. In some embodiments, the heterocycle has 3-18 ring members inwhich one or more ring members is a heteroatom independently selectedfrom oxygen, sulfur or nitrogen, and each ring in the system contains 3to 7 ring members. In other embodiments, a heterocycle may be amonocycle having 3-7 ring members (2-6 carbon atoms and 1-4 heteroatoms)or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6heteroatoms). Examples of bicyclic heterocyclic ring systems include,but are not limited to: adamantanyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl.

As used herein, the term “heterocycle” also includes polycyclic ringsystems wherein the heterocyclic ring is fused with one or more aromaticor non-aromatic carbocyclic or heterocyclic rings, or with combinationsthereof, as long as the radical or point of attachment is on theheterocyclic ring.

Examples of heterocyclic rings include, but are not limited to, thefollowing monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino,3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the followingbicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

As used herein, the term “aryl” (as in “aryl ring” or “aryl group”),used alone or as part of a larger moiety, as in “aralkyl”, “aralkoxy”,“aryloxyalkyl”, refers to a carbocyclic ring system wherein at least onering in the system is aromatic and has a single point of attachment tothe rest of the molecule. Unless otherwise specified, an aryl group maybe monocyclic, bicyclic or tricyclic and contain 6-18 ring members. Theterm also includes polycyclic ring systems where the aryl ring is fusedwith one or more aromatic or non-aromatic carbocyclic or heterocyclicrings, or with combinations thereof, as long as the radical or point ofattachment is in the aryl ring. Examples of aryl rings include, but arenot limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl,and anthracenyl.

The term “aralkyl” refers to a radical having an aryl ring substitutedwith an alkylene group, wherein the open end of the alkylene groupallows the aralkyl radical to bond to another part of the compound ofFormula I. The alkylene group is a bivalent, straight-chain or branched,saturated hydrocarbon group. As used herein, the term “C₇₋₁₂ aralkyl”means an aralkyl radical wherein the total number of carbon atoms in thearyl ring and the alkylene group combined is 7 to 12. Examples of“aralkyl” include, but not limited to, a phenyl ring substituted by aC₁₋₆ alkylene group, e.g., benzyl and phenylethyl, and a naphthyl groupsubstituted by a C₁₋₂ alkylene group.

The term “heteroaryl” (or “heteroaromatic” or “heteroaryl group” or“aromatic heterocycle”) used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy” refers to a ring system wherein atleast one ring in the system is aromatic and contains one or moreheteroatoms, wherein each ring in the system contains 3 to 7 ringmembers and which has a single point of attachment to the rest of themolecule. Unless otherwise specified, a heteroaryl ring system may bemonocyclic, bicyclic or tricyclic and have a total of five to fourteenring members. In one embodiment, all rings in a heteroaryl system arearomatic. Also included in this definition are heteroaryl radicals wherethe heteroaryl ring is fused with one or more aromatic or non-aromaticcarbocyclic or heterocyclic rings, or combinations thereof, as long asthe radical or point of attachment is in the heteroaryl ring. Bicyclic6, 5 heteroaromatic system, as used herein, for example, is a sixmembered heteroaromatic ring fused to a second five membered ringwherein the radical or point of attachment is on the six-membered ring.

Heteroaryl rings include, but are not limited to the followingmonocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl,4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl(e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl(e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl,benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl,quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), andisoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or4-isoquinolinyl).

As used herein, “cyclo” (or “cyclic”, or “cyclic moiety”) encompassesmono-, bi- and tri-cyclic ring systems including cycloaliphatic,heterocyclic, aryl or heteroaryl, each of which has been previouslydefined.

“Fused” bicyclic ring systems comprise two rings which share twoadjoining ring atoms.

“Bridged” bicyclic ring systems comprise two rings which share three orfour adjacent ring atoms. As used herein, the term “bridge” refers to anatom or a chain of atoms connecting two different parts of a molecule.The two atoms that are connected through the bridge (usually but notalways, two tertiary carbon atoms) are referred to as “bridgeheads”. Inaddition to the bridge, the two bridgeheads are connected by at leasttwo individual atoms or chains of atoms. Examples of bridged bicyclicring systems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. “Spiro” bicyclic ring systems shareonly one ring atom (usually a quaternary carbon atom) between the tworings.

The term “ring atom” refers to an atom such as C, N, O or S that is partof the ring of an aromatic ring, a cycloaliphatic ring, a heterocyclicor a heteroaryl ring. A “substitutable ring atom” is a ring carbon ornitrogen atom bonded to at least one hydrogen atom. The hydrogen can beoptionally replaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atomswhich are shared when two rings are fused. In addition, “substitutablering atom” does not include ring carbon or nitrogen atoms when thestructure depicts that they are already attached to one or more moietyother than hydrogen and no hydrogens are available for substitution.

“Heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,phosphorus, or silicon, the quaternized form of any basic nitrogen, or asubstitutable nitrogen of a heterocyclic or heteroaryl ring, for exampleN (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

In some embodiments, two independent occurrences of a variable may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered, heterocyclyl, aryl, or heteroaryl ring or a 3-8-memberedcycloaliphatic ring. Exemplary rings that are formed when twoindependent occurrences of a substituent are taken together with theatom(s) to which each variable is bound include, but are not limited tothe following: a) two independent occurrences of a substituent that arebound to the same atom and are taken together with that atom to form aring, where both occurrences of the substituent are taken together withthe atom to which they are bound to form a heterocyclyl, heteroaryl,cycloaliphatic or aryl ring, wherein the group is attached to the restof the molecule by a single point of attachment; and b) two independentoccurrences of a substituent that are bound to different atoms and aretaken together with both of those atoms to form a heterocyclyl,heteroaryl, cycloaliphatic or aryl ring, wherein the ring that is formedhas two points of attachment with the rest of the molecule. For example,where a phenyl group is substituted with two occurrences of —OR^(o) asin Formula D1:

these two occurrences of —OR^(o) are taken together with the carbonatoms to which they are bound to form a fused 6-membered oxygencontaining ring as in Formula D2:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of a substituent are taken together with theatom(s) to which each substituent is bound and that the examplesdetailed above are not intended to be limiting.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain can optionally be replaced with saidother atom or group. Unless otherwise specified, the optionalreplacements form a chemically stable compound. Optional interruptionscan occur both within the chain and/or at either end of the chain; i.e.both at the point of attachment(s) to the rest of the molecule and/or atthe terminal end. Two optional replacements can also be adjacent to eachother within a chain so long as it results in a chemically stablecompound. Unless otherwise specified, if the replacement or interruptionoccurs at a terminal end of the chain, the replacement atom is bound toan H on the terminal end. For example, if —CH₂CH₂CH₃ were optionallyinterrupted with —O—, the resulting compound could be —OCH₂CH₃,—CH₂OCH₃, or —CH₂CH₂OH. In another example, if the divalent linker—CH₂CH₂CH₂— were optionally interrupted with —O—, the resulting compoundcould be —OCH₂CH₂—, —CH₂OCH₂—, or —CH₂CH₂O—. The optional replacementscan also completely replace all of the carbon atoms in a chain. Forexample, a C₃ aliphatic can be optionally replaced by —N(R′)—, —C(O)—,and —N(R′)— to form —N(R′)C(O)N(R′)— (a urea).

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent at the end of the substituentbound to the rest of the chemical structure. Alkylcarboxy (e.g.,alkyl-C(O)O— or alkyl-O(CO)—) and alkylcarboxyaryl (e.g.,alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groupsused internally.

As described herein, a bond drawn from a substituent to the center ofone ring within a multiple-ring system (as shown below), representssubstitution of the substituent at any substitutable position in any ofthe rings within the multiple ring system. For example, formula D3represents possible substitution in any of the positions shown informula D4:

This also applies to multiple ring systems fused to optional ringsystems (which would be represented by dotted lines). For example, inFormula D5, X is an optional substituent both for ring A and ring B.

If, however, two rings in a multiple ring system each have differentsubstituents drawn from the center of each ring, then, unless otherwisespecified, each substituent only represents substitution on the ring towhich it is attached. For example, in Formula D6, Y is an optionalsubstituent for ring A only, and X is an optional substituent for ring Bonly.

As used herein, the terms “alkoxy” or “alkylthio” refer to an alkylgroup, as previously defined, attached to the molecule, or to anotherchain or ring, through an oxygen (“alkoxy” i.e., —O-alkyl) or a sulfur(“alkylthio” i.e., —S-alkyl) atom.

The terms C_(n-m) “alkoxyalkyl”, C_(n-m) “alkoxyalkenyl”, C_(n-m)“alkoxyaliphatic”, and C_(n-m) “alkoxyalkoxy” mean alkyl, alkenyl,aliphatic or alkoxy, as the case may be, substituted with one or morealkoxy groups, wherein the combined total number of carbons of the alkyland alkoxy groups, alkenyl and alkoxy groups, aliphatic and alkoxygroups or alkoxy and alkoxy groups, combined, as the case may be, isbetween the values of n and m. For example, a C₄₋₆ alkoxyalkyl has atotal of 4-6 carbons divided between the alkyl and alkoxy portion; e.g.it can be —CH₂OCH₂CH₂CH₃, —CH₂CH₂OCH₂CH₃ or —CH₂CH₂CH₂OCH₃.

When the moieties described in the preceding paragraph are optionallysubstituted, they can be substituted in either or both of the portionson either side of the oxygen or sulfur. For example, an optionallysubstituted C₄ alkoxyalkyl could be, for instance, —CH₂CH₂OCH₂(Me)CH₃ or—CH₂(OH)OCH₂CH₂CH₃; a C₅ alkoxyalkenyl could be, for instance, —CH═CHOCH₂CH₂CH₃ or —CH═CHCH₂OCH₂CH₃.

The terms aryloxy, arylthio, benzyloxy or benzylthio, refer to an arylor benzyl group attached to the molecule, or to another chain or ring,through an oxygen (“aryloxy”, benzyloxy e.g., —O-Ph, —OCH₂Ph) or sulfur(“arylthio” e.g., —S-Ph, —S—CH₂Ph) atom. Further, the terms“aryloxyalkyl”, “benzyloxyalkyl” “aryloxyalkenyl” and “aryloxyaliphatic”mean alkyl, alkenyl or aliphatic, as the case may be, substituted withone or more aryloxy or benzyloxy groups, as the case may be. In thiscase, the number of atoms for each aryl, aryloxy, alkyl, alkenyl oraliphatic will be indicated separately. Thus, a 5-6-memberedaryloxy(C₁₋₄alkyl) is a 5-6 membered aryl ring, attached via an oxygenatom to a C₁₋₄ alkyl chain which, in turn, is attached to the rest ofthe molecule via the terminal carbon of the C₁₋₄ alkyl chain.

As used herein, the terms “halogen” or “halo” mean F, Cl, Br, or I.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be,substituted with one or more halogen atoms. For example a C₁₋₃ haloalkylcould be —CFHCH₂CHF₂ and a C₁₋₂ haloalkoxy could be —OC(Br)HCHF₂. Thisterm includes perfluorinated alkyl groups, such as —CF₃ and —CF₂CF₃.

As used herein, the term “cyano” refers to —CN or —C≡N.

The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and“cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more cyano groups. For example a C₁₋₃cyanoalkyl could be —C(CN)₂CH₂CH₃ and a C₁₋₂ cyanoalkenyl could be═CHC(CN)H₂.

As used herein, an “amino” group refers to —NH₂.

The terms “aminoalkyl”, “aminoalkenyl”, “aminoaliphatic”, and“aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more amino groups. For example a C₁₋₃aminoalkyl could be —CH(NH₂)CH₂CH₂NH₂ and a C₁₋₂ aminoalkoxy could be—OCH₂CH₂NH₂.

The term “hydroxyl” or “hydroxy” refers to —OH.

The terms “hydroxyalkyl”, “hydroxyalkenyl”, “hydroxyaliphatic”, and“hydroxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the casemay be, substituted with one or more —OH groups. For example a C₁₋₃hydroxyalkyl could be —CH₂(CH₂OH)CH₃ and a C₄ hydroxyalkoxy could be—OCH₂C(CH₃)(OH)CH₃.

As used herein, a “carbonyl”, used alone or in connection with anothergroup refers to —C(O)— or —C(O)H. For example, as used herein, an“alkoxycarbonyl,” refers to a group such as —C(O)O(alkyl).

As used herein, an “oxo” refers to ═O, wherein oxo is usually, but notalways, attached to a carbon atom (e.g., it can also be attached to asulfur atom). An aliphatic chain can be optionally interrupted by acarbonyl group or can optionally be substituted by an oxo group, andboth expressions refer to the same: e.g. —CH₂—C(O)—CH₃.

As used herein, in the context of resin chemistry (e.g. using solidresins or soluble resins or beads), the term “linker” refers to abifunctional chemical moiety attaching a compound to a solid support orsoluble support.

In all other situations, a “linker”, as used herein, refers to adivalent group in which the two free valences are on different atoms(e.g. carbon or heteroatom) or are on the same atom but can besubstituted by two different substituents. For example, a methylenegroup can be C₁ alkyl linker (—CH₂—) which can be substituted by twodifferent groups, one for each of the free valences (e.g. as inPh-CH₂-Ph, wherein methylene acts as a linker between two phenyl rings).Ethylene can be C₂ alkyl linker (—CH₂CH₂—) wherein the two free valencesare on different atoms. The amide group, for example, can act as alinker when placed in an internal position of a chain (e.g. —CONH—). Alinker can be the result of interrupting an aliphatic chain by certainfunctional groups or of replacing methylene units on said chain by saidfunctional groups. E.g. a linker can be a C₁₋₆ aliphatic chain in whichup to two methylene units are substituted by —C(O)— or —NH— (as in—CH₂—NH—CH₂—C(O)—CH₂— or —CH₂—NH—C(O)—CH₂—). An alternative way todefine the same —CH₂—NH—CH₂—C(O)—CH₂— and —CH₂—NH—C(O)—CH₂— groups is asa C₃ alkyl chain optionally interrupted by up to two —C(O)— or —NH—moieties. Cyclic groups can also form linkers: e.g. a1,6-cyclohexanediyl can be a linker between two R groups, as in

A linker can additionally be optionally substituted in any portion orposition.

Divalent groups of the type R—CH═ or R₂C═, wherein both free valencesare in the same atom and are attached to the same substituent, are alsopossible. In this case, they will be referred to by their IUPAC acceptednames. For instance an alkylidene (such as, for example, a methylidene(═CH₂) or an ethylidene (═CH—CH₃)) would not be encompassed by thedefinition of a linker in this disclosure.

The term “protecting group”, as used herein, refers to an agent used totemporarily block one or more desired reactive sites in amultifunctional compound. In certain embodiments, a protecting group hasone or more, or preferably all, of the following characteristics: a)reacts selectively in good yield to give a protected substrate that isstable to the reactions occurring at one or more of the other reactivesites; and b) is selectively removable in good yield by reagents that donot attack the regenerated functional group. Exemplary protecting groupsare detailed in Greene, T. W. et al., “Protective Groups in OrganicSynthesis”, Third Edition, John Wiley & Sons, New York: 1999, the entirecontents of which is hereby incorporated by reference. The term“nitrogen protecting group”, as used herein, refers to an agents used totemporarily block one or more desired nitrogen reactive sites in amultifunctional compound. Preferred nitrogen protecting groups alsopossess the characteristics exemplified above, and certain exemplarynitrogen protecting groups are detailed in Chapter 7 in Greene, T. W.,Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition,John Wiley & Sons, New York: 1999, the entire contents of which arehereby incorporated by reference.

As used herein, the term “displaceable moiety” or “leaving group” refersto a group that is associated with an aliphatic or aromatic group asdefined herein and is subject to being displaced by nucleophilic attackby a nucleophile.

As used herein, “amide coupling agent” or “amide coupling reagent” meansa compound that reacts with the hydroxyl moiety of a carboxy moietythereby rendering it susceptible to nucleophilic attack. Exemplary amidecoupling agents include DIC (diisopropylcarbodiimide), EDCI(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC(dicyclohexylcarbodiimide), BOP(benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate), pyBOP((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate),etc.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Compound Embodiments

The present invention is directed to compounds of Formula I, orpharmaceutically acceptable salts thereof,

wherein:

-   ring B is a 5-membered heteroaryl ring selected from furan or    thiophene;-   n is an integer selected from 0 to 3;-   each J^(B) is independently selected from halogen, —CN, a C₁₋₆    aliphatic, —OR^(B) or a C₃₋₈ cycloaliphatic group; wherein each said    C₁₋₆ aliphatic and each said C₃₋₈ cycloaliphatic group is optionally    and independently substituted with up to 3 instances of R³;-   each R^(B) is independently selected from hydrogen, a C₁₋₆ aliphatic    or a C₃₋₈ cycloaliphatic ring; wherein each said C₁₋₆ aliphatic and    each said C₃₋₈ cycloaliphatic ring is optionally and independently    substituted with up to 3 instances of R^(3a);-   each R³ is independently selected from halogen, —CN, C₁₋₄ alkyl,    C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);-   each R^(3a) is independently selected from halogen, —CN, C₁₋₄ alkyl,    C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);-   X is selected from N, C-J^(D) or C—H;-   o is an integer selected from 0 to 3;-   each J^(D) is independently selected from halogen, —NO₂, —OR^(D),    —SR^(D), —C(O)R^(D), —C(O)OR^(D), —C(O)N(R^(D))₂, —CN, —N(R^(D))₂,    —N(R^(d))C(O)R^(D), —N(R^(d))C(O)OR^(D), —SO₂R^(D), SO₂N(R^(D))₂,    —N(R^(d))SO₂R^(D), a C₁₋₆ aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈    cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to 8-membered    heterocyclic ring or a 5 to 10-membered heteroaryl ring; wherein    each said 4 to 8-membered heterocylic ring and each said 5 to    10-membered heteroaryl ring contains between 1 and 3 heteroatoms    independently selected from O, N or S; and wherein each said C₁₋₆    aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 6 to    10-membered aryl ring, each said 4 to 8-membered heterocyclic ring    and each said 5 to 10-membered heteroaryl ring is optionally and    independently substituted with up to 3 instances of R⁵;-   each R^(D) is independently selected from hydrogen, a C₁₋₆    aliphatic, —(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4    to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered    heteroaryl ring; wherein each said 4 to 8-membered heterocylic ring    and each said 5 to 6-membered heteroaryl ring contains between 1 and    3 heteroatoms independently selected from O, N or S; and wherein    each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring, each    said 4 to 8-membered heterocyclic ring, each said phenyl and each    said 5 to 6-membered heteroaryl ring is optionally and independently    substituted with up to 3 instances of R^(5a);-   each R^(d) is independently selected from hydrogen, a C₁₋₆    aliphatic, —(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4    to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered    heteroaryl ring; wherein each said heterocylic ring and each said    heteroaryl ring contains between 1 and 3 heteroatoms independently    selected from O, N or S; and wherein each said C₁₋₆ aliphatic, each    said C₃₋₈ cycloaliphatic ring, each said 4 to 8-membered    heterocyclic ring, each said phenyl and each said 5 to 6-membered    heteroaryl ring is optionally and independently substituted by up to    3 instances of R^(5b);-   each R^(f) is independently selected from a C₃₋₈ cycloaliphatic    ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to    6-membered heteroaryl ring; wherein each said heterocylic ring and    each said heteroaryl ring contains between 1 and 3 heteroatoms    independently selected from O, N or S; and wherein each said C₁₋₆    aliphatic, each said C₃₋₈ cycloaliphatic ring, each said 4 to    8-membered heterocyclic ring, each said phenyl and each said 5 to    6-membered heteroaryl ring is optionally and independently    substituted by up to 3 instances of R^(5c);-   when J^(D) is —C(O)N(R^(D))₂, —N(R^(D))₂ or —SO₂N(R^(D))₂, the two    instances of R^(D) together with the nitrogen atom attached to the    R^(D), alternatively form a 4 to 8-membered heterocyclic ring or a    5-membered heteroaryl ring; wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring    optionally contains up to 2 additional heteroatoms independently    selected from N, O or S, and wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring is    optionally and independently substituted by up to 3 instances of R⁵;    or-   when J^(D) is —N(R^(d))C(O)R^(D), the R^(D) group together with the    carbon atom attached to the R^(D) group, with the nitrogen atom    attached to the R^(d) group and with the R^(d) group alternatively    form a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl    ring; wherein each said 4 to 8-membered heterocyclic ring and each    said 5-membered heteroaryl ring optionally contains up to 2    additional heteroatoms independently selected from N, O or S, and    wherein each said 4 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring is optionally and independently    substituted by up to 3 instances of R⁵;-   when J^(D) is —N(R^(d))C(O)OR^(D), the R^(D) group together with the    oxygen atom attached to the R^(D) group, with the carbon atom of the    —C(O)— portion of the —N(R^(d))C(O)OR^(D) group, with the nitrogen    atom attached to the R^(d) group, and with the R^(d) group    alternatively form a 4 to 8-membered heterocyclic ring or a    5-membered heteroaryl ring; wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring    optionally contains up to 2 additional heteroatoms independently    selected from N, O or S, and wherein each said 4 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring is    optionally and independently substituted by up to 3 instances of R⁵;-   when J^(D) is —N(R^(d))SO₂R^(D), the R^(D) group together with the    oxygen atom attached to the R^(D) group, with the sulfur atom    attached to said oxygen atom in the —SO₂R^(D) portion of the    N(R^(d))SO₂R^(D) group, with the nitrogen atom attached to the R^(d)    group, and with the R^(d) group alternatively form a 4 to 8-membered    heterocyclic ring or a 5-membered heteroaryl ring; wherein each said    4 to 8-membered heterocyclic ring and each said 5-membered    heteroaryl ring optionally contains up to 2 additional heteroatoms    independently selected from N, O or S, and wherein each said 4 to    8-membered heterocyclic ring and each said 5-membered heteroaryl    ring is optionally and independently substituted by up to 3    instances of R⁵;-   each R⁵ is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(5a) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(5b) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(5c) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄    cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an    oxo group; wherein each said phenyl group is optionally and    independently substituted with up to 3 instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and wherein each    said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R⁶ is independently selected from hydrogen, a C₁₋₄ alkyl, a    C₂₋₄ alkenyl, phenyl, a C₇₋₁₂ aralkyl or a C₃₋₈ cycloalkyl ring;    wherein each said C₁₋₄ alkyl, each said C₂₋₄ alkenyl, each said    phenyl, each said C₇₋₁₂ aralkyl and each said C₃₋₈ cycloalkyl group    is optionally and independently substituted with up to 3 instances    of halogen;-   alternatively, two instances of R⁶ linked to the same nitrogen atom    of R⁵, together with said nitrogen atom of R⁵, form a 5 to    8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 5 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S; or-   alternatively, one instance of R⁶ linked to a nitrogen atom of R⁵    and one instance of R⁶ linked to a carbon or sulfur atom of the same    R⁵, together with said nitrogen and said carbon or sulfur atom of    the same R⁵, form a 5 to 8-membered heterocyclic ring or a    5-membered heteroaryl ring; wherein each said 5 to 8-membered    heterocyclic ring and each said 5-membered heteroaryl ring    optionally contains up to 2 additional heteroatoms independently    selected from N, O or S;-   or, alternatively, two J^(D) groups attached to two vicinal ring D    atoms, taken together with said two vicinal ring D atoms, form a 5    to 7-membered heterocycle resulting in a fused ring D wherein said 5    to 7-membered heterocycle contains from 1 to 3 heteroatoms    independently selected from N, O or S; and wherein said 5 to    7-membered heterocycle is optionally and independently substituted    by up to 3 instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄    alkyl)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl), —O(C₁₋₄    haloalkyl), oxo or phenyl; wherein said phenyl is optionally and    independently substituted by up to three instances of halogen, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄    haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl);-   R^(C) is a ring C; ring C is a phenyl ring, a monocyclic 5 or    6-membered heteroaryl ring, a bicyclic 8 to 10-membered heteroaryl    ring, a monocyclic 3 to 10-membered cycloaliphatic ring, or a    monocyclic 4 to 10-membered heterocycle; wherein said monocyclic 5    or 6-membered heteroaryl ring, said bicyclic 8 to 10-membered    heteroaryl ring, or said monocyclic 4 to 10-membered heterocycle    contain between 1 and 4 heteroatoms selected from N, O or S; wherein    said monocyclic 5 or 6-membered heteroaryl ring is not a    1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5 to    6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl    ring, or monocyclic 4 to 10-membered heterocycle is optionally and    independently substituted with up to 3 instances of J^(C);-   each J^(C) is independently selected from halogen, —CN, —NO₂, a C₁₋₆    aliphatic, —OR^(H), —SR^(H), —N(R^(H))₂, a C₃₋₈ cycloaliphatic ring    or a 4 to 8-membered heterocyclic ring; wherein said 4 to 8-membered    heterocyclic ring contains 1 or 2 heteroatoms independently selected    from N, O or S; wherein each said C₁₋₆ aliphatic, each said C₃₋₈    cycloaliphatic ring and each said 4 to 8-membered heterocyclic ring,    is optionally and independently substituted with up to 3 instances    of R⁷; or alternatively, two J^(C) groups attached to two vicinal    ring C atoms, taken together with said two vicinal ring C atoms,    form a 5 to 7-membered heterocycle resulting in a fused ring C;    wherein said 5 to 7-membered heterocycle contains from 1 to 2    heteroatoms independently selected from N, O or S;-   each R^(H) is independently selected from hydrogen, a C₁₋₆    aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to 8-membered    heterocyclic ring; wherein each said 4 to 8-membered heterocylic    ring contains between 1 and 3 heteroatoms independently selected    from O, N or S; and wherein each said C₁₋₆ aliphatic, each said C₃₋₈    cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, is    optionally and independently substituted with up to 3 instances of    R^(7a);-   alternatively, two instances of R^(H) linked to the same nitrogen    atom of J^(C), together with said nitrogen atom of J^(C), form a 4    to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 4 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S, and wherein each    said 4 to 8-membered heterocyclic ring and each said 5-membered    heteroaryl ring is optionally and independently substituted by up to    3 instances of R^(7b); or-   each R⁷ is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or    an oxo group; wherein each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(7a) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or    an oxo group; wherein each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R^(7b) is independently selected from halogen, —CN, —NO₂, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or    an oxo group; wherein each said cycloalkyl group is optionally and    independently substituted with up to 3 instances of halogen;-   each R⁸ is independently selected from hydrogen, a C₁₋₄ alkyl, C₁₋₄    haloalkyl or a C₃₋₈ cycloalkyl ring; wherein each said cycloalkyl    group is optionally and independently substituted with up to 3    instances of halogen;-   alternatively, two instances of R⁸ linked to the same nitrogen atom    of R⁷, together with said nitrogen atom of R⁷, form a 5 to    8-membered heterocyclic ring or a 5-membered heteroaryl ring;    wherein each said 5 to 8-membered heterocyclic ring and each said    5-membered heteroaryl ring optionally contains up to 2 additional    heteroatoms independently selected from N, O or S; and-   R^(A) is selected from hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄    haloalkyl.

In some embodiments of Formula I, ring B is thiophene. In someembodiments, said thiophene ring is a 3-thiophenyl ring. In otherembodiments it is a 2-thiophenyl ring. In some embodiments, saidthiophene ring is unsubstituted and n=0. In other embodiments, saidthiophene is substituted and n is an integer selected from 1, 2 or 3.

In some embodiments of Formula I wherein ring B is substitutedthiophene, each J^(B) is independently selected from halogen, a C₁₋₆aliphatic or —OR^(B). In other embodiments, each J^(B) is independentlyselected from a halogen atom. In some embodiments, when J^(B) isindependently selected from a halogen atom, each J^(B) can beindependently selected from fluoro or chloro, or each J^(B) is fluoro.In other embodiments, each J^(B) is independently selected from a C₁₋₆aliphatic. In some embodiments, each J^(B) is methyl or ethyl. In otherembodiments, each J^(B) is methyl. In still other embodiments of FormulaI, wherein ring B is substituted thiophene, each J^(B) is independentlyselected from —OR^(B); wherein each R^(B) is hydrogen or a C₁₋₆ alkyl.In some embodiments, each R^(B) is methyl, ethyl, propyl or isopropyl.

In some of the above embodiments, wherein ring B is substitutedthiophene, n is 1 or 2 and each J^(B) is independently selected fromfluoro, chloro, methyl or methoxy. In other embodiments, ring B is amono substituted thiophene and J^(B) is fluoro.

In some of the embodiments of Formula I, wherein ring B is thiophene,unsubstituted or substituted, X is N so that ring D is pyrimidine,unsubstituted or substituted. Ring B can be 2-thiophenyl or3-thiophenyl.

In some of the embodiments of Formula I, R^(C) is 1,2-oxazole or1,3-oxazole, unsubstituted or substituted.

In some of the embodiments of Formula I, wherein ring B is thiophene,unsubstituted or substituted, X is N so that ring D is pyrimidine,unsubstituted or substituted, and R^(C) is 1,3-oxazole or 1,2-oxazole,unsubstituted or substituted.

In other embodiments of Formula I, ring B is a furan ring. In someembodiments, n=0 and the furan ring in unsubstituted. In otherembodiments, ring B is a substituted furan ring and n is an integerselected from 1 and 2. In some of the above embodiments, wherein ring Bis substituted furan, n is 1 or 2 and each J^(B) is independentlyselected from fluoro, chloro, methyl or methoxy. In other embodiments,ring B is a mono substituted furan and J^(B) is fluoro.

In some of the embodiments of Formula I, wherein ring B is furan,unsubstituted or substituted, X is C-J^(D) or C—H, so that ring D ispyridine unsubstituted or substituted. Ring B can be 2-furanyl or3-furanyl.

In some of the embodiments of Formula I, wherein ring B is furan,unsubstituted or substituted, X is C-J^(D) or C—H, so that ring D ispyridine unsubstituted or substituted, and R^(C) is 1,3-oxazole or1,2-oxazole, unsubstituted or substituted.

In some embodiments of Formula I, X in ring D is C-J^(D) or C—H. Inother embodiments X in ring D is N.

In some embodiments of Formula I, ring D is unsubstituted and o is 0. Inother embodiments of Formula I, o is an integer selected from 1 to 3.

In those embodiments of Formula I wherein ring D is substituted, eachJ^(D) is independently selected from halogen, a C₁₋₆ aliphatic,—N(R^(D))₂, —N(R^(d))C(O)R^(D), —N(R^(d))C(O)OR^(D),N(R^(d))C(O)N(R^(D))₂, —SO₂R^(D), —SO₂N(R^(D))₂, —N(R^(d))SO₂R^(D),—SR^(D), —OR^(D) or an optionally substituted C₃₋₈ cycloaliphatic ring.In some of the above embodiments, wherein ring D is substituted, o is 1.In other embodiments, o is 2. In other embodiments o is 3.

In some embodiments of Formula I, wherein ring D is substituted, o is 1,2 or 3 and each J^(D) is independently selected from methyl, chloro,fluoro, —N(R^(D))₂, or —OR^(D); wherein each R^(D) is independentlyselected from hydrogen or methyl. In other embodiments, o is 1 or 2 andeach J^(D) is independently selected from fluoro, hydroxyl or amino.

In some embodiments of Formula I, R^(C) is a phenyl ring, a monocyclic 5to or 6-membered heteroaryl ring, a monocyclic 3 to 10-memberedcycloaliphatic ring or a monocyclic 4 to 10-membered heterocycle; eachof them optionally and independently substituted by up to 6 instances ofJ^(C). In other embodiments of Formula I, ring C is a phenyl ring, amonocyclic 5 to 6-membered heteroaryl ring, a monocyclic 3 to 6-memberedcycloaliphatic ring or a monocyclic 4 to 6-membered heterocycle; each ofthem optionally and independently substituted with up to 3 instances ofJ^(C).

In some embodiments of Formula I, R^(C) is a monocyclic 3 to 6-memberedcycloaliphatic ring, optionally and independently substituted with up to2 instances of J^(C). In other embodiments, ring C is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl. In other embodiments of FormulaI, R^(C) is a ring C which is a 4-membered cycloaliphatic ringsubstituted by 1 to 3 instances of J^(C), a 5-membered cycloaliphaticring substituted by 1 to 4 instances of J^(C) or a 6-memberedcycloaliphatic ring substituted by 1 to 5 instances of J^(C); whereineach J^(C) is independently selected from halogen or a C₁₋₆ aliphatic.

In other embodiments of Formula I, R^(C) is phenyl, optionally andindependently substituted by up to 5 instances of J^(C). In someembodiments, ring C is phenyl and it is unsubstituted. In otherembodiments, it is substituted by 1 to 3 instances of J^(C); whereineach J^(C) is independently selected from halogen, a C₁₋₆ aliphatic,—NH₂, —CN or —O(C₁₋₆ aliphatic). In other embodiments, each J^(C) isindependently selected from halogen, —NH₂, —CN, C₁₋₆ alkyl or —O(C₁₋₄alkyl). In still other embodiments, ring C is phenyl substituted by 1 to2 instances of J^(C) and each J^(C) is selected from fluoro, chloro,methyl, —CN or —OCH₃.

In still other embodiments of Formula I, R^(C) is a 5 to 6-memberedheteroaryl ring and is optionally and independently substituted by up to5 instances of J^(C). In some embodiments, said 5 to 6-memberedheteroaryl ring is unsubstituted. In other embodiments, it issubstituted with 1 to 3 instances of J^(C). In some of theseembodiments, the 5 to 6-membered heteroaryl ring can be selected fromthienyl, thiazolyl, oxadiazolyl, oxazolyl, isooxazolyl, tetrazolyl,pyrrolyl, triazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl. In yet other embodiments, ring C is an isoxazole ring andit is unsubstituted.

In some embodiments of Formula I, ring C is a 5 to 6-membered heteroarylring and it is substituted by 1 to 5 instances of J^(C); wherein eachJ^(C) is independently selected from halogen, a C₁₋₆ aliphatic, —CN,—NH₂ or —O(C₁₋₆ aliphatic).

In some embodiments, the compounds of the invention are represented bystructural Formula IIA or IIB:

wherein J^(B) is selected from hydrogen or a halogen. In someembodiments the halogen is fluoro.

In some embodiments of Formulae IIA and IIB, X in ring D is C—H. Inother embodiments X in ring D is N.

In some embodiments of Formulae IIA and IIB, ring D is unsubstituted ando is 0. In other embodiments of Formulae IIA and IIB, o is an integerfrom 1 to 3.

In those embodiments of Formula IIA and IIB wherein ring D issubstituted, each J^(D) is independently selected from halogen, a C₁₋₆aliphatic, —N(R^(D))₂, —OR^(D) or an optionally substituted C₃₋₈cycloaliphatic ring. In other embodiments, n is 2 and each J^(D) isindependently selected from a halogen atom or —NH₂ or —OH. In stillother embodiments, n is 2 and one instance of J^(D) is fluoro and theother one is —OH. In other embodiments, n is 1 and J^(D) is —NH₂.

In other embodiments of Formulae IIA and IIB, R^(C) is phenyl,optionally and independently substituted by up to 5 instances of J^(C).In some embodiments, ring C is phenyl and it is unsubstituted. In otherembodiments, it is substituted by 1 to 3 instances of J^(C); whereineach J^(C) is independently selected from halogen, a C₁₋₆ aliphatic,—NH₂, —CN or —O(C₁₋₆ aliphatic). In other embodiments, each J^(C) isindependently selected from halogen,

-   -   NH₂, —CN, C₁₋₆ alkyl or —O(C₁₋₄ alkyl). In still other        embodiments, ring C is phenyl substituted by 1 to 2 instances of        J^(C) and each J^(C) is selected from fluoro, chloro, methyl,        —CN or —OCH₃.

In still other embodiments of Formulae IIA and IIB, R^(C) is a 5 to6-membered heteroaryl ring and is optionally and independentlysubstituted by up to 5 instances of J^(C). In some embodiments, said 5to 6-membered heteroaryl ring is unsubstituted. In other embodiments, itis substituted with 1 to 3 instances of J^(C). In some of theseembodiments, the 5 to 6-membered heteroaryl ring can be selected fromthienyl, thiazolyl, oxadiazolyl, oxazolyl, isooxazolyl, tetrazolyl,pyrrolyl, triazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl. In other embodiments, the heteroaryl ring C is selectedfrom isoxazolyl, furanyl, thienyl, thiazolyl, 1,3,4-oxadiazolyl,pyridinyl, pyrimidinyl or pyrazin-3-yl. In still other embodiments, theheteroaryl ring C is selected from isoxazolyl, thienyl, thiazolyl,1,3,4-oxadiazolyl or pyridinyl. In other embodiments, ring C is a 5-6membered heteroaryl and it is substituted by 1 or 2 instances of J^(C);wherein each J^(C) is selected from fluoro, chloro, bromo, methyl, —CN,—NH₂ or —OCH₃. In yet other embodiments of Formula IIA and IIB, ring Cis an isoxazole and it is unsubstituted.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

In some embodiments, compounds of Formula I are selected from thoselisted in Table 1.

TABLE 1

I-1

I-2

I-3

I-4

I-5

Methods of Preparing the Compounds

The compounds of Formula I may be prepared according to the schemes andexamples depicted and described below. Unless otherwise specified, thestarting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available compounds orprepared using well-known synthetic methods. Another aspect of thepresent invention is a process for preparing the compounds of Formula Ias disclosed herein.

General synthetic procedures for the compounds of this invention aredescribed below. The synthetic schemes are presented as examples and donot limit the scope of the invention in any way.

General Procedure A

Step 1: Dione Enolate Formation:

To a solution of ketone A in THF cooled to −78° C., LiHMDS (e.g., 0.9eq, 1.0 M in toluene) is added dropwise via syringe. The reaction isthen allowed to warm to 0° C., then charged with diethyl oxalate (1.2eq). At this time, the reaction is warmed to room temperature andstirred at that temperature until judged complete (e.g., using eitherTLC or LC/MS analysis). Once the reaction is complete (reaction time wastypically 45 minutes), the product dione enolate B is used as-is in Step2, i.e., the cyclization step, without any further purification.

Step 2: Pyrazole Formation:

Dione enolate B is diluted with ethanol and consecutively charged withHCl (e.g., 3 eq, 1.25M solution in ethanol) and arylhydrazine hydrate(e.g., 1.15 eq). The reaction mixture is heated to 70° C. and stirreduntil cyclization is deemed complete (e.g., by LC/MS analysis, typically30 minutes). Once complete, the reaction mixture is treated carefullywith solid sodium bicarbonate (e.g., 4 eq) and diluted withdichloromethane and water. Layers are separated, and aqueous layer isfurther diluted with water before extraction with dichloromethane (3×).The combined organics are washed with brine, dried over MgSO4, filtered,and concentrated in vacuo. The resulting pyrazole C is then purified bySiO₂ chromatography using an appropriate gradient of EtOAc in hexanes.

Step 3: Amidine Formation:

To a suspension of NH₄Cl (e.g., 5 eq) in toluene cooled to 0° C. isadded AlMe₃ (e.g., 5 eq, 2.0M solution in toluene) dropwise via syringe.Reaction is allowed to warm to room temperature, and stirred until nomore bubbling is observed. Pyrazole C is added in 1 portion to thereaction, heated to 110° C., and stirred at this temperature untiljudged complete (e.g., using either TLC or LC/MS analysis). Oncecomplete, reaction is cooled, treated with excess methanol, and stirredvigorously for 1 hour at room temperature. The thick slurry is filtered,and the resulting solid cake is washed with methanol. The filtrate isconcentrated in vacuo, and the resulting solids are re-suspended in anethyl acetate:isopropyl alcohol=5:1 solvent mixture. The reaction isfurther treated with saturated sodium carbonate solution, and stirredfor 10 minutes before the layers are separated. The aqueous layer isextracted with the ethyl acetate:isopropyl alcohol=5:1 solvent mixture(3×), and the combined organics are washed with brine. The organics arefurther dried over MgSO4, filtered, and the solvent is removed in vacuo.The product amidine D is used as-is in subsequent steps without furtherpurification. See more details in the Example section.

Pharmaceutically Acceptable Salts of the Invention.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofFormula I. The pharmaceutically acceptable salts of a compound ofFormula I are used in medicine. Salts that are not pharmaceuticallyacceptable may, however, be useful in the preparation of a compound ofFormula I or of their pharmaceutically acceptable salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counter ion.The counter ion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counter ions. Hence, apharmaceutically acceptable salt can have one or more charged atomsand/or one or more counter ion.

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from the compounds with inorganic acids, organicacids or bases. In some embodiments, the salts can be prepared in situduring the final isolation and purification of the compounds. In otherembodiments the salts can be prepared from the free form of the compoundin a separate synthetic step.

When a compound of Formula I is acidic or contains a sufficiently acidicbioisostere, suitable “pharmaceutically acceptable salts” refers tosalts prepared form pharmaceutically acceptable non-toxic basesincluding inorganic bases and organic bases. Salts derived frominorganic bases include aluminum, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic salts, manganous, potassium,sodium, zinc and the like. Particular embodiments include ammonium,calcium, magnesium, potassium and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as arginine, betaine, caffeine, choline, N,N.sup.1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine tripropylamine, tromethamineand the like.

When a compound of Formula I is basic or contains a sufficiently basicbioisostere, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Particular embodiments includecitric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric andtartaric acids. Other exemplary salts include, but are not limited, tosulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19, incorporated here by reference in its entirety.

In addition to the compounds described herein, their pharmaceuticallyacceptable salts may also be employed in compositions to treat orprevent the herein identified disorders.

Pharmaceutical Compositions and Methods of Administration.

The compounds herein disclosed, and their pharmaceutically acceptablesalts thereof may be formulated as pharmaceutical compositions or“formulations”.

A typical formulation is prepared by mixing a compound of Formula I, ora pharmaceutically acceptable salt thereof, and a carrier, diluent orexcipient. Suitable carriers, diluents and excipients are well known tothose skilled in the art and include materials such as carbohydrates,waxes, water soluble and/or swellable polymers, hydrophilic orhydrophobic materials, gelatin, oils, solvents, water, and the like. Theparticular carrier, diluent or excipient used will depend upon the meansand purpose for which a compound of Formula I is being formulated.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS-Generally Regarded as Safe) to beadministered to a mammal. In general, safe solvents are non-toxicaqueous solvents such as water and other non-toxic solvents that aresoluble or miscible in water. Suitable aqueous solvents include water,ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300),etc. and mixtures thereof. The formulations may also include other typesof excipients such as one or more buffers, stabilizing agents,antiadherents, surfactants, wetting agents, lubricating agents,emulsifiers, binders, suspending agents, disintegrants, fillers,sorbents, coatings (e.g. enteric or slow release) preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents and other known additivesto provide an elegant presentation of the drug (i.e., a compound ofFormula I or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of Formula I, a pharmaceutically acceptable salt thereof, or astabilized form of the compound, such as a complex with a cyclodextrinderivative or other known complexation agent) is dissolved in a suitablesolvent in the presence of one or more of the excipients describedabove. A compound having the desired degree of purity is optionallymixed with pharmaceutically acceptable diluents, carriers, excipients orstabilizers, in the form of a lyophilized formulation, milled powder, oran aqueous solution. Formulation may be conducted by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers. The pH of the formulationdepends mainly on the particular use and the concentration of compound,but may range from about 3 to about 8. When the agent described hereinis a solid amorphous dispersion formed by a solvent process, additivesmay be added directly to the spray-drying solution when forming themixture such as the additive is dissolved or suspended in the solutionas a slurry which can then be spray dried. Alternatively, the additivesmay be added following spray-drying process to aid in the forming of thefinal formulated product.

The compound of Formula I or a pharmaceutically acceptable salt thereofis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed regimen. Pharmaceutical formulations of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, may beprepared for various routes and types of administration. Various dosageforms may exist for the same compound, since different medicalconditions may warrant different routes of administration.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thesubject treated and the particular mode of administration. For example,a time-release formulation intended for oral administration to humansmay contain approximately 1 to 1000 mg of active material compoundedwith an appropriate and convenient amount of carrier material which mayvary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provideeasily measurable amounts for administration. For example, an aqueoussolution intended for intravenous infusion may contain from about 3 to500 μg of the active ingredient per milliliter of solution in order thatinfusion of a suitable volume at a rate of about 30 mL/hr can occur. Asa general proposition, the initial pharmaceutically effective amount ofthe inhibitor administered will be in the range of about 0.01-100 mg/kgper dose, namely about 0.1 to 20 mg/kg of patient body weight per day,with the typical initial range of compound used being 0.3 to 15mg/kg/day.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician. The therapeutically or pharmaceutically effectiveamount of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to ameliorate, cureor treat the disease or disorder or one or more of its symptoms.

The pharmaceutical compositions of Formula I will be formulated, dosed,and administered in a fashion, i.e., amounts, concentrations, schedules,course, vehicles, and route of administration, consistent with goodmedical practice. Factors for consideration in this context include theparticular disorder being treated, the particular mammal being treated,the clinical condition of the individual patient, the cause of thedisorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners, such as the age, weight, and response ofthe individual patient.

The term “prophylactically effective amount” refers to an amounteffective in preventing or substantially lessening the chances ofacquiring a disease or disorder or in reducing the severity of thedisease or disorder before it is acquired or reducing the severity ofone or more of its symptoms before the symptoms develop. Roughly,prophylactic measures are divided between primary prophylaxis (toprevent the development of a disease) and secondary prophylaxis (wherebythe disease has already developed and the patient is protected againstworsening of this process).

Acceptable diluents, carriers, excipients, and stabilizers are thosethat are nontoxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, citrate, and otherorganic acids; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride, benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol);proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, tretralose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g. Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). The active pharmaceutical ingredients mayalso be entrapped in microcapsules prepared, for example, bycoacervation techniques or by interfacial polymerization, e.g.,hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacylate) microcapsules, respectively; in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nanoparticles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's: The Science and Practiceof Pharmacy, 21^(st) Edition, University of the Sciences inPhiladelphia, Eds., 2005 (hereafter “Remington's”).

“Controlled drug delivery systems” supply the drug to the body in amanner precisely controlled to suit the drug and the conditions beingtreated. The primary aim is to achieve a therapeutic drug concentrationat the site of action for the desired duration of time. The term“controlled release” is often used to refer to a variety of methods thatmodify release of drug from a dosage form. This term includespreparations labeled as “extended release”, “delayed release”, “modifiedrelease” or “sustained release”. In general, one can provide forcontrolled release of the agents described herein through the use of awide variety of polymeric carriers and controlled release systemsincluding erodible and non-erodible matrices, osmotic control devices,various reservoir devices, enteric coatings and multiparticulate controldevices.

“Sustained-release preparations” are the most common applications ofcontrolled release. Suitable examples of sustained-release preparationsinclude semipermeable matrices of solid hydrophobic polymers containingthe compound, which matrices are in the form of shaped articles, e.g.films, or microcapsules. Examples of sustained-release matrices includepolyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate),or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers, and poly-D-(−)-3-hydroxybutyric acid.

“Immediate-release preparations” may also be prepared. The objective ofthese formulations is to get the drug into the bloodstream and to thesite of action as rapidly as possible. For instance, for rapiddissolution, most tablets are designed to undergo rapid disintegrationto granules and subsequent deaggregation to fine particles. Thisprovides a larger surface area exposed to the dissolution medium,resulting in a faster dissolution rate.

Agents described herein can be incorporated into an erodible ornon-erodible polymeric matrix controlled release device. By an erodiblematrix is meant aqueous-erodible or water-swellable or aqueous-solublein the sense of being either erodible or swellable or dissolvable inpure water or requiring the presence of an acid or base to ionize thepolymeric matrix sufficiently to cause erosion or dissolution. Whencontacted with the aqueous environment of use, the erodible polymericmatrix imbibes water and forms an aqueous-swollen gel or matrix thatentraps the agent described herein. The aqueous-swollen matrix graduallyerodes, swells, disintegrates or dissolves in the environment of use,thereby controlling the release of a compound described herein to theenvironment of use. One ingredient of this water-swollen matrix is thewater-swellable, erodible, or soluble polymer, which may generally bedescribed as an osmopolymer, hydrogel or water-swellable polymer. Suchpolymers may be linear, branched, or cross linked. The polymers may behomopolymers or copolymers. In certain embodiments, they may besynthetic polymers derived from vinyl, acrylate, methacrylate, urethane,ester and oxide monomers. In other embodiments, they can be derivativesof naturally occurring polymers such as polysaccharides (e.g. chitin,chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locustbean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthangum and scleroglucan), starches (e.g. dextrin and maltodextrin),hydrophilic colloids (e.g. pectin), phosphatides (e.g. lecithin),alginates (e.g. ammonium alginate, sodium, potassium or calciumalginate, propylene glycol alginate), gelatin, collagen, andcellulosics. Cellulosics are cellulose polymer that has been modified byreaction of at least a portion of the hydroxyl groups on the sacchariderepeat units with a compound to form an ester-linked or an ether-linkedsubstituent. For example, the cellulosic ethyl cellulose has an etherlinked ethyl substituent attached to the saccharide repeat unit, whilethe cellulosic cellulose acetate has an ester linked acetatesubstituent. In certain embodiments, the cellulosics for the erodiblematrix comprises aqueous-soluble and aqueous-erodible cellulosics caninclude, for example, ethyl cellulose (EC), methylethyl cellulose (MEC),carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulosepropionate (CP), cellulose butyrate (CB), cellulose acetate butyrate(CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), andethylhydroxy ethylcellulose (EHEC). In certain embodiments, thecellulosics comprises various grades of low viscosity (MW less than orequal to 50,000 daltons, for example, the Dow Methocel™ series E5,E15LV, E50LV and K100LY) and high viscosity (MW greater than 50,000daltons, for example, E4MCR, E10MCR, K4M, K15M and K100M and theMethocel™ K series) HPMC. Other commercially available types of HPMCinclude the Shin Etsu Metolose 90SH series.

Other materials useful as the erodible matrix material include, but arenot limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl acetate, glycerol fatty acid esters, polyacrylamide,polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acidderivatives such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl)methacrylate chloride.

Alternatively, the agents of the present invention may be administeredby or incorporated into a non-erodible matrix device. In such devices,an agent described herein is distributed in an inert matrix. The agentis released by diffusion through the inert matrix. Examples of materialssuitable for the inert matrix include insoluble plastics (e.g methylacrylate-methyl methacrylate copolymers, polyvinyl chloride,polyethylene), hydrophilic polymers (e.g. ethyl cellulose, celluloseacetate, cross linked polyvinylpyrrolidone (also known ascrospovidone)), and fatty compounds (e.g. carnauba wax, microcrystallinewax, and triglycerides). Such devices are described further inRemington: The Science and Practice of Pharmacy, 20th edition (2000).

As noted above, the agents described herein may also be incorporatedinto an osmotic control device. Such devices generally include a corecontaining one or more agents as described herein and a water permeable,non-dissolving and non-eroding coating surrounding the core whichcontrols the influx of water into the core from an aqueous environmentof use so as to cause drug release by extrusion of some or all of thecore to the environment of use. In certain embodiments, the coating ispolymeric, aqueous-permeable, and has at least one delivery port. Thecore of the osmotic device optionally includes an osmotic agent whichacts to imbibe water from the surrounding environment via such asemipermeable membrane. The osmotic agent contained in the core of thisdevice may be an aqueous-swellable hydrophilic polymer or it may be anosmogen, also known as an osmagent. Pressure is generated within thedevice which forces the agent(s) out of the device via an orifice (of asize designed to minimize solute diffusion while preventing the build-upof a hydrostatic pressure head). Non limiting examples of osmoticcontrol devices are disclosed in U.S. patent application Ser. No.09/495,061.

The amount of water-swellable hydrophilic polymers present in the coremay range from about 5 to about 80 wt % (including for example, 10 to 50wt %). Non limiting examples of core materials include hydrophilic vinyland acrylic polymers, polysaccharides such as calcium alginate,polyethylene oxide (PEO), polyethylene glycol (PEG), polypropyleneglycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid,poly (methacrylic) acid, polyvinylpyrrolidone (PVP) and cross linkedPVP, polyvinyl alcohol (PVA), PVA/PVP copolymers and PVA/PVP copolymerswith hydrophobic monomers such as methyl methacrylate, vinyl acetate,and the like, hydrophilic polyurethanes containing large PEO blocks,sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodiumalginate, polycarbophil, gelatin, xanthan gum, and sodium starchglycolat. Other materials include hydrogels comprising interpenetratingnetworks of polymers that may be formed by addition or by condensationpolymerization, the components of which may comprise hydrophilic andhydrophobic monomers such as those just mentioned. Water-swellablehydrophilic polymers include but are not limited to PEO, PEG, PVP,sodium croscarmellose, HPMC, sodium starch glycolate, polyacrylic acidand cross linked versions or mixtures thereof.

The core may also include an osmogen (or osmagent). The amount ofosmogen present in the core may range from about 2 to about 70 wt %(including, for example, from 10 to 50 wt %). Typical classes ofsuitable osmogens are water-soluble organic acids, salts and sugars thatare capable of imbibing water to thereby effect an osmotic pressuregradient across the barrier of the surrounding coating. Typical usefulosmogens include but are not limited to magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassiumchloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol,raffinose, sucrose, glucose, fructose, lactose, citric acid, succinicacid, tartaric acid, and mixtures thereof. In certain embodiments, theosmogen is glucose, lactose, sucrose, mannitol, xylitol, sodiumchloride, including combinations thereof.

The rate of drug delivery is controlled by such factors as thepermeability and thickness of the coating, the osmotic pressure of thedrug-containing layer, the degree of hydrophilicity of the hydrogellayer, and the surface area of the device. Those skilled in the art willappreciate that increasing the thickness of the coating will reduce therelease rate, while any of the following will increase the release rate:increasing the permeability of the coating; increasing thehydrophilicity of the hydrogel layer; increasing the osmotic pressure ofthe drug-containing layer; or increasing the device's surface area.

In certain embodiments, entrainment of particles of agents describedherein in the extruding fluid during operation of such osmotic device isdesirable. For the particles to be well entrained, the agent drug formis dispersed in the fluid before the particles have an opportunity tosettle in the tablet core. One means of accomplishing this is by addinga disintegrant that serves to break up the compressed core into itsparticulate components. Non limiting examples of standard disintegrantsinclude materials such as sodium starch glycolate (e. g., Explotab™CLV), microcrystalline cellulose (e. g., Avicel™), microcrystallinesilicified cellulose (e. g., ProSoIv™) and croscarmellose sodium (e. g.,Ac-Di-Sol™), and other disintegrants known to those skilled in the art.Depending upon the particular formulation, some disintegrants workbetter than others. Several disintegrants tend to form gels as theyswell with water, thus hindering drug delivery from the device.Non-gelling, non-swelling disintegrants provide a more rapid dispersionof the drug particles within the core as water enters the core. Incertain embodiments, non-gelling, non-swelling disintegrants are resins,for example, ion-exchange resins. In one embodiment, the resin isAmberlite™ IRP 88 (available from Rohm and Haas, Philadelphia, Pa.).When used, the disintegrant is present in amounts ranging from about1-25% of the core agent.

Another example of an osmotic device is an osmotic capsule. The capsuleshell or portion of the capsule shell can be semipermeable. The capsulecan be filled either by a powder or liquid consisting of an agentdescribed herein, excipients that imbibe water to provide osmoticpotential, and/or a water-swellable polymer, or optionally solubilizingexcipients. The capsule core can also be made such that it has a bilayeror multilayer agent analogous to the bilayer, trilayer or concentricgeometries described above.

Another class of osmotic device useful in this invention comprisescoated swellable tablets, for example, as described in EP378404. Coatedswellable tablets comprise a tablet core comprising an agent describedherein and a swelling material, preferably a hydrophilic polymer, coatedwith a membrane, which contains holes, or pores through which, in theaqueous use environment, the hydrophilic polymer can extrude and carryout the agent. Alternatively, the membrane may contain polymeric or lowmolecular weight water-soluble porosigens. Porosigens dissolve in theaqueous use environment, providing pores through which the hydrophilicpolymer and agent may extrude. Examples of porosigens are water-solublepolymers such as HPMC, PEG, and low molecular weight compounds such asglycerol, sucrose, glucose, and sodium chloride. In addition, pores maybe formed in the coating by drilling holes in the coating using a laseror other mechanical means. In this class of osmotic devices, themembrane material may comprise any film-forming polymer, includingpolymers which are water permeable or impermeable, providing that themembrane deposited on the tablet core is porous or containswater-soluble porosigens or possesses a macroscopic hole for wateringress and drug release. Embodiments of this class of sustained releasedevices may also be multilayered, as described, for example, inEP378404.

When an agent described herein is a liquid or oil, such as a lipidvehicle formulation, for example as described in WO05/011634, theosmotic controlled-release device may comprise a soft-gel or gelatincapsule formed with a composite wall and comprising the liquidformulation where the wall comprises a barrier layer formed over theexternal surface of the capsule, an expandable layer formed over thebarrier layer, and a semipermeable layer formed over the expandablelayer. A delivery port connects the liquid formulation with the aqueoususe environment. Such devices are described, for example, in U.S. Pat.No. 6,419,952, U.S. Pat. No. 6,342,249, U.S. Pat. No. 5,324,280, U.S.Pat. No. 4,672,850, U.S. Pat. No. 4,627,850, U.S. Pat. No. 4,203,440,and U.S. Pat. No. 3,995,631.

As further noted above, the agents described herein may be provided inthe form of microparticulates, generally ranging in size from about 10μm to about 2 mm (including, for example, from about 100 μm to 1 mm indiameter). Such multiparticulates may be packaged, for example, in acapsule such as a gelatin capsule or a capsule formed from anaqueous-soluble polymer such as HPMCAS, HPMC or starch; dosed as asuspension or slurry in a liquid; or they may be formed into a tablet,caplet, or pill by compression or other processes known in the art. Suchmultiparticulates may be made by any known process, such as wet- anddry-granulation processes, extrusion/spheronization, roller-compaction,melt-congealing, or by spray-coating seed cores. For example, in wet-and dry-granulation processes, the agent described herein and optionalexcipients may be granulated to form multiparticulates of the desiredsize.

The agents can be incorporated into microemulsions, which generally arethermodynamically stable, isotropically clear dispersions of twoimmiscible liquids, such as oil and water, stabilized by an interfacialfilm of surfactant molecules (Encyclopedia of Pharmaceutical Technology,New York: Marcel Dekker, 1992, volume 9). For the preparation ofmicroemulsions, surfactant (emulsifier), co-surfactant (co-emulsifier),an oil phase and a water phase are necessary. Suitable surfactantsinclude any surfactants that are useful in the preparation of emulsions,e.g., emulsifiers that are typically used in the preparation of creams.The co-surfactant (or “co-emulsifier”) is generally selected from thegroup of polyglycerol derivatives, glycerol derivatives and fattyalcohols. Preferred emulsifier/co-emulsifier combinations are generallyalthough not necessarily selected from the group consisting of: glycerylmonostearate and polyoxyethylene stearate; polyethylene glycol andethylene glycol palmitostearate; and caprilic and capric triglyceridesand oleoyl macrogolglycerides. The water phase includes not only waterbut also, typically, buffers, glucose, propylene glycol, polyethyleneglycols, preferably lower molecular weight polyethylene glycols (e.g.,PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phasewill generally comprise, for example, fatty acid esters, modifiedvegetable oils, silicone oils, mixtures of mono- di- and triglycerides,mono- and di-esters of PEG (e.g., oleoyl macrogol glycerides), etc.

The compounds described herein can be incorporated intopharmaceutically-acceptable nanoparticle, nanosphere, and nanocapsuleformulations (Delie and Blanco-Prieto, 2005, Molecule 10:65-80).Nanocapsules can generally entrap compounds in a stable and reproducibleway. To avoid side effects due to intracellular polymeric overloading,ultrafine particles (sized around 0.1 μm) can be designed using polymersable to be degraded in vivo (e.g. biodegradable polyalkyl-cyanoacrylatenanoparticles). Such particles are described in the prior art.

Implantable devices coated with a compound of this invention are anotherembodiment of the present invention. The compounds may also be coated onimplantable medical devices, such as beads, or co-formulated with apolymer or other molecule, to provide a “drug depot”, thus permittingthe drug to be released over a longer time period than administration ofan aqueous solution of the drug. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccharides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's. Such methods include the step of bringing into associationthe active ingredient with the carrier which constitutes one or moreaccessory ingredients. In general the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and then,if necessary, shaping the product.

The terms “administer”, “administering” or “administration” in referenceto a compound, composition or formulation of the invention meansintroducing the compound into the system of the animal in need oftreatment. When a compound of the invention is provided in combinationwith one or more other active agents, “administration” and its variantsare each understood to include concurrent and/or sequential introductionof the compound and the other active agents.

The compositions described herein may be administered systemically orlocally, e.g.: orally (e.g. using capsules, powders, solutions,suspensions, tablets, sublingual tablets and the like), by inhalation(e.g. with an aerosol, gas, inhaler, nebulizer or the like), to the ear(e.g. using ear drops), topically (e.g. using creams, gels, liniments,lotions, ointments, pastes, transdermal patches, etc), ophthalmically(e.g. with eye drops, ophthalmic gels, ophthalmic ointments), rectally(e.g. using enemas or suppositories), nasally, buccally, vaginally (e.g.using douches, intrauterine devices, vaginal suppositories, vaginalrings or tablets, etc), via an implanted reservoir or the like, orparenterally depending on the severity and type of the disease beingtreated. The term “parenteral” as used herein includes, but is notlimited to, subcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intraperitoneally orintravenously.

The pharmaceutical compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. Liquiddosage forms for oral administration include, but are not limited to,pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to mask an unpleasant taste orto delay disintegration and adsorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed. A water soluble taste maskingmaterial such as hydroxypropyl-methylcellulose orhydroxypropyl-cellulose may be employed.

Formulations of a compound of Formula I that are suitable for oraladministration may be prepared as discrete units such as tablets, pills,troches, lozenges, aqueous or oil suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, e.g. gelatin capsules,syrups or elixirs. Formulations of a compound intended for oral use maybe prepared according to any method known to the art for the manufactureof pharmaceutical compositions.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above.

When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Syrupsand elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

Sterile injectable forms of the compositions described herein (e.g. forparenteral administration) may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or di-glycerides. Fatty acids, such as oleicacid and its glyceride derivatives are useful in the preparation ofinjectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions may also contain a long-chain alcoholdiluent or dispersant, such as carboxymethyl cellulose or similardispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms including emulsions andsuspensions. Other commonly used surfactants, such as Tweens, Spans andother emulsifying agents or bioavailability enhancers which are commonlyused in the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of injectableformulations.

Oily suspensions may be formulated by suspending a compound of Formula Iin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Aqueous suspensions of a compound of Formula I contain the activematerials in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients include a suspending agent, such assodium carboxymethylcellulose, croscarmellose, povidone,methylcellulose, hydroxypropyl methylcelluose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound described herein, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsulated matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

The injectable solutions or microemulsions may be introduced into apatient's bloodstream by local bolus injection. Alternatively, it may beadvantageous to administer the solution or microemulsion in such a wayas to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds describedherein with suitable non-irritating excipients or carriers such as cocoabutter, beeswax, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound. Other formulations suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprays.

The pharmaceutical compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the ear, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel. Topical applicationfor the lower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum. For treatment of theeye or other external tissues, e.g., mouth and skin, the formulationsmay be applied as a topical ointment or cream containing the activeingredient(s) in an amount of, for example, 0.075 to 20% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither an oil-based, paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include a polyhydric alcohol, i.e. an alcohol having two ormore hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of emulsions prepared using a compound of Formula I maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier (otherwise known as an emulgent), itdesirably comprises a mixture of at least one emulsifier with a fat oran oil or with both a fat and an oil. A hydrophilic emulsifier may beincluded together with a lipophilic emulsifier which acts as astabilizer. In some embodiments, the emulsifier includes both an oil anda fat. Together, the emulsifier(s) with or without stabilizer(s) make upthe so-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations. Emulgents and emulsionstabilizers suitable for use in the formulation of a compound of FormulaI include Tween′-60, Span′-80, cetostearyl alcohol, benzyl alcohol,myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

The pharmaceutical compositions may also be administered by nasalaerosol or by inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents. Formulations suitable for intrapulmonary or nasal administrationhave a particle size for example in the range of 0.1 to 500 micros(including particles in a range between 0.1 and 500 microns inincrements microns such as 0.5, 1, 30, 35 microns, etc) which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs.

The pharmaceutical composition (or formulation) for use may be packagedin a variety of ways depending upon the method used for administeringthe drug. Generally, an article for distribution includes a containerhaving deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

In another aspect, a compound of Formula I or a pharmaceuticallyacceptable salt thereof may be formulated in a veterinary compositioncomprising a veterinary carrier. Veterinary carriers are materialsuseful for the purpose of administering the composition and may besolid, liquid or gaseous materials which are otherwise inert or acceptFormula In the veterinary art and are compatible with the activeingredient. These veterinary compositions may be administeredparenterally, orally or by any other desired route.

Therapeutic Methods

The present disclosure relates to stimulators of soluble guanylatecyclase (sGC), pharmaceutical formulations thereof and their use, aloneor in combination with one or more additional agents, for treatingand/or preventing various diseases, wherein an increase in theconcentration of NO or an increase in the concentration of cGMP might bedesirable. The diseases that can be treated include but are not limitedtopulmonary hypertension, arterial hypertension, heart failure,atherosclerosis, inflammation, thrombosis, renal fibrosis and failure,liver cirrhosis, erectile dysfunction and other related cardiovasculardisorders.

Increased concentration of cGMP leads to vasodilation, inhibition ofplatelet aggregation and adhesion, anti-hypertensive effects,anti-remodeling effects, anti-apoptotic effects, anti-inflammatoryeffects and neuronal signal transmission effects. Thus, sGC stimulatorsmay be used to treat and/or prevent a range of diseases and disorders,including but not limited to a peripheral, pulmonary, hepatic, liver,cardiac or cerebralvascular/endothelial disorders or conditions, aurogenital-gynecological disorder or condition, a thromboembolicdisease, a fibrotic disorder, a pulmonary or respiratory disorder, arenal or hepatic disorder, a metabolic disorder, atherosclerosis, or alipid related disorder.

In other embodiments, the compounds here disclosed are sGC stimulatorsthat may be useful in the prevention and/or treatment of diseases anddisorders characterized by undesirable reduced bioavailability of and/orsensitivity to NO, such as those associated with conditions of oxidativestress or nitrosative stress.

Throughout this disclosure, the terms “hypertension”, “arterialhypertension” or “high blood pressure (HBP)” are used interchangeableand refer to an extremely common and highly preventable chroniccondition in which blood pressure (BP) in the arteries is higher thannormal. If not properly controlled, it represents a significant riskfactor for several serious cardiovascular and renal conditions.Hypertension may be a primary disease, called “essential hypertension”or “idiopathic hypertension”, or it may be caused by other diseases, inwhich case it is classified as “secondary hypertension”. Essentialhypertension accounts for 90-95% of all cases.

As used herein, the term “resistant hypertension” refers to hypertensionthat remains above goal blood pressure (usually less than 140/90 mmHg,although a lower goal of less than 130/80 mmHg is recommended forpatients with comorbid diabetes or kidney disease), in spite ofconcurrent use of three antihypertensive agents belonging to differentantihypertensive drug classes. People who require four or more drugs tocontrol their blood pressure are also considered to have resistanthypertension.

Hypertension is an extremely common comorbid condition in diabetes,affecting ˜20-60% of patients with diabetes, depending on obesity,ethnicity, and age. This type of hypertension is herein referred to as“diabetic hypertension”. In type 2 diabetes, hypertension is oftenpresent as part of the metabolic syndrome of insulin resistance alsoincluding central obesity and dyslipidemia. In type 1 diabetes,hypertension may reflect the onset of diabetic nephropathy.

“Pulmonary hypertension (PH)”, as used herein, is a diseasecharacterized by sustained elevations of blood pressure in the pulmonaryvasculature (pulmonary artery, pulmonary vein and pulmonarycapillaries), which results in right heart hypertrophy, eventuallyleading to right heart failure and death. Common symptoms of PH includeshortness of breath, dizziness and fainting, all of which areexacerbated by exertion. Without treatment, median life expectancyfollowing diagnosis is 2.8 years. PH exists in many different forms,which are categorized according to their etiology. Categories includepulmonary arterial hypertension (PAH), PH with left heart disease, PHassociated with lung diseases and/or hypoxaemia, PH due to chronicthrombotic and/or embolic disease and miscellaneous PH. PAH is rare inthe general population, but the prevalence increases in association withcertain common conditions such as HIV infection, scleroderma and sicklecell disease. Other forms of PH are generally more common than PAH, and,for instance, the association of PH with chronic obstructive pulmonarydisease (COPD) is of particular concern. Current treatment for pulmonaryhypertension depends on the stage and the mechanism of the disease.

As used herein “heart failure” is a progressive disorder of leftventricular (LV) myocardial remodeling that culminates in a complexclinical syndrome in which impaired cardiac function and circulatorycongestion are the defining features, and results in insufficientdelivery of blood and nutrients to body tissues. The condition occurswhen the heart is damaged or overworked and unable to pump out all theblood that returns to it from the systemic circulation. As less blood ispumped out, blood returning to the heart backs up and fluid builds up inother parts of the body. Heart failure also impairs the kidneys' abilityto dispose of sodium and water, complicating fluid retention further.Heart failure is characterized by autonomic dysfunction, neurohormonalactivation and overproduction of cytokines, which contribute toprogressive circulatory failure. Symptoms of heart failure include:dyspnea (shortness of breath) while exercising or resting and waking atnight due to sudden breathlessness, both indicative of pulmonary edema;general fatigue or weakness, edema of the feet, ankles and legs, rapidweight gain, chronic cough, including that producing mucus or blood.Depending on its clinical presentation, heart failure is classified asde novo, transient or chronic. Acute heart failure, i.e. the rapid orgradual onset of symptoms requiring urgent therapy, may develop de novoor as a result of chronic heart failure becoming decompensated. Diabetesis a common comorbidity in patients with heart failure and is associatedwith poorer outcomes as well as potentially compromising the efficacy oftreatments. Other important comorbidities include systemic hypertension,chronic airflow obstruction, sleep apnea, cognitive dysfunction, anemia,chronic kidney disease and arthritis. Chronic left heart failure isfrequently associated with the development of pulmonary hypertension.The frequency of certain comorbidities varies by gender: among women,hypertension and thyroid disease are more common, while men morecommonly suffer from chronic obstructive pulmonary disease (COPD),peripheral vascular disease, coronary artery disease and renalinsufficiency. Depression is a frequent comorbidity of heart failure andthe two conditions can and often do complicate one another. Cachexia haslong been recognized as a serious and frequent complication of heartfailure, affecting up to 15% of all heart failure patients and beingassociated with poor prognosis. Cardiac cachexia is defined as thenonedematous, nonvoluntary loss of at least 6% of body weight over aperiod of six months.

The term “sleep apnea” refers to the most common of the sleep-disorderedbreathing disorders. It is a condition characterized by intermittent,cyclical reductions or total cessations of airflow, which may or may notinvolve obstruction of the upper airway. There are three types of sleepapnea: obstructive sleep apnea, the most common form, central sleepapnea and mixed sleep apnea.

“Central sleep apnea (CSA)”, is caused by a malfunction in the brain'snormal signal to breathe, rather than physical blockage of the airway.The lack of respiratory effort leads to an increase in carbon dioxide inthe blood, which may rouse the patient. CSA is rare in the generalpopulation, but is a relatively common occurrence in patients withsystolic heart failure.

As used herein, the term “metabolic syndrome”, “insulin resistancesyndrome” or “syndrome X”, refers to a group or clustering of metabolicconditions (abdominal obesity, elevated fasting glucose, “dyslipidemia”(i.e, elevated lipid levels) and elevated blood pressure (HBP)) whichoccur together more often than by chance alone and that together promotethe development of type 2 diabetes and cardiovascular disease. Metabolicsyndrome is characterized by a specific lipid profile of increasedtriglycerides, decreased high-density lipoprotein cholesterol(HDL-cholesterol) and in some cases moderately elevated low-densitylipoprotein cholesterol (LDL-cholesterol) levels, as well as acceleratedprogression of “atherosclerotic disease” due to the pressure of thecomponent risk factors. There are several types of dyslipidemias:“hypercholesterolemia” refers to elevated levels of cholesterol.Familial hypercholesterolemia is a specific form of hypercholesterolemiadue to a defect on chromosome 19 (19p13.1-13.3). “Hyperglyceridemia”refers to elevated levels of glycerides (e.g., “hypertrigliceridemia”involves elevated levels of triglycerides). “Hyperlipoproteinemia”refers to elevated levels of lipoproteins (usually LDL unless otherwisespecified).

As used herein, the term “peripheral vascular disease (PVD)”, alsocommonly referred to as “peripheral arterial disease (PAD)” or“peripheral artery occlusive disease (PAOD)”, refers to the obstructionof large arteries not within the coronary, aortic arch vasculature, orbrain. PVD can result from atherosclerosis, inflammatory processesleading to stenosis, an embolism, or thrombus formation. It causeseither acute or chronic “ischemia (lack of blood supply)”. Often PVD isa term used to refer to atherosclerotic blockages found in the lowerextremity. PVD also includes a subset of diseases classified asmicrovascular diseases resulting from episodal narrowing of the arteries(e.g., “Raynaud's phenomenon”), or widening thereof (erythromelalgia),i.e. vascular spasms.

The term “thrombosis” refers to the formation of a blood clot(“thrombus”) inside a blood vessel, obstructing the flow of bloodthrough the circulatory system. When a blood vessel is injured, the bodyuses platelets (thrombocytes) and fibrin to form a blood clot to preventblood loss. Alternatively, even when a blood vessel is not injured,blood clots may form in the body if the proper conditions presentthemselves. If the clotting is too severe and the clot breaks free, thetraveling clot is now known as an “embolus”. The term “thromboembolism”refers to the combination of thrombosis and its main complication,“embolism”. When a thrombus occupies more than 75% of surface area ofthe lumen of an artery, blood flow to the tissue supplied is reducedenough to cause symptoms because of decreased oxygen (hypoxia) andaccumulation of metabolic products like lactic acid (“gout”). More than90% obstruction can result in anoxia, the complete deprivation ofoxygen, and “infarction”, a mode of cell death.

An “embolism” (plural embolisms) is the event of lodging of an embolus(a detached intravascular mass capable of clogging arterial capillarybeds at a site far from its origin) into a narrow capillary vessel of anarterial bed which causes a blockage (vascular occlusion) in a distantpart of the body. This is not to be confused with a thrombus whichblocks at the site of origin.

A “stroke”, or cerebrovascular accident (CVA), is the rapid loss ofbrain function(s) due to disturbance in the blood supply to the brain.This can be due to “ischemia” (lack of blood flow) caused by blockage(thrombosis, arterial embolism), or a hemorrhage (leakage of blood). Asa result, the affected area of the brain cannot function, which mightresult in an inability to move one or more limbs on one side of thebody, inability to understand or formulate speech, or an inability tosee one side of the visual field. Risk factors for stroke include oldage, hypertension, previous stroke or transient ischemic attack (TIA),diabetes, high cholesterol, cigarette smoking and atrial fibrillation.High blood pressure is the most important modifiable risk factor ofstroke. An “ischemic stroke” is occasionally treated in a hospital withthrombolysis (also known as a “clot buster”), and some hemorrhagicstrokes benefit from neurosurgery. Prevention of recurrence may involvethe administration of antiplatelet drugs such as aspirin anddipyridamole, control and reduction of hypertension, and the use ofstatins. Selected patients may benefit from carotid endarterectomy andthe use of anticoagulants.

“Ischemia” is a restriction in blood supply to tissues, causing ashortage of oxygen and glucose needed for cellular metabolism (to keeptissue alive). Ischemia is generally caused by problems with bloodvessels, with resultant damage to or dysfunction of tissue. It alsomeans local anemia in a given part of a body sometimes resulting fromcongestion (such as vasoconstriction, thrombosis or embolism).

According to the American Psychiatric Association's Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition (DSM-IV), theterm “sexual dysfunction” encompasses a series of conditions“characterized by disturbances in sexual desire and in thepsychophysiological changes associated with the sexual response cycle”;while problems of this type are common, sexual dysfunction is onlyconsidered to exist when the problems cause distress for the patient.Sexual dysfunction can be either physical or psychological in origin. Itcan exist as a primary condition, generally hormonal in nature, althoughmost often it is secondary to other medical conditions or to drugtherapy for said conditions. All types of sexual dysfunction can befurther classified as life-long, acquired, situational or generalized(or combinations thereof).

The DSM-IV-TR specifies five major categories of “female sexualdysfunction”: sexual desire/interest disorders; “sexual arousaldisorders (including genital, subjective and combined)”; orgasmicdisorder; dyspareunia and vaginismus; and persistent sexual arousaldisorder.

“Female sexual arousal disorder (FSAD)” is defined as a persistent orrecurring inability to attain or maintain sufficient levels of sexualexcitement, causing personal distress. FSAD encompasses both the lack ofsubjective feelings of excitement (i.e., subjective sexual arousaldisorder) and the lack of somatic responses such as lubrication andswelling (i.e., genital/physical sexual arousal disorder). FSAD may bestrictly psychological in origin, although it generally is caused orcomplicated by medical or physiological factors. Hypoestrogenism is themost common physiologic condition associated with FSAD, which leads tourogenital atrophy and a decrease in vaginal lubrication.

As used herein, “erectile dysfunction (ED)” is a male sexual dysfunctioncharacterized by the inability to develop or maintain an erection of thepenis during sexual performance. A penile erection is the hydrauliceffect of blood entering and being retained in sponge-like bodies withinthe penis. The process is often initiated as a result of sexual arousal,when signals are transmitted from the brain to nerves in the penis.Erectile dysfunction is indicated when an erection is difficult toproduce. The most important organic causes are cardiovascular diseaseand diabetes, neurological problems (for example, trauma fromprostatectomy surgery), hormonal insufficiencies (hypogonadism) and drugside effects.

Specific diseases of disorders which may be treated and/or prevented byadministering an sGC stimulator of the invention, include but are notlimited to: hypertension (e.g., diabetic hypertension, arterialhypertension, pulmonary hypertension, resistant hypertension, peripheralartery disease, etc), heart failure (e.g., left ventricular diastolicdysfunction (LVDD) and left ventricular systolic dysfunction (LVSD),sleep apnea associated with heart failure), arteriosclerotic disease(e.g., atherosclerosis), thromboembolic disorders (e.g., chronicthromboembolic pulmonary hypertension, thrombosis, stroke, embolism,pulmonary embolism), renal diseases (e.g., renal fibrosis, ischemicrenal disease, renal failure, renal insufficiency, chronic kidneydisease), hepatic disease (e.g., liver fibrosis or cirrhosis),respiratory disease (e.g., pulmonary fibrosis, asthma, chronicobstructive pulmonary disease, interstitial lung disease), sexualdisorders (e.g., erectile dysfunction, male and female sexualdysfunction, vaginal atrophy), sickle cell anemia, neuro inflammatorydiseases or disorders and metabolic disorders (e.g., lipid relateddisorders).

The compounds of Formula I as well as pharmaceutically acceptable saltsthereof, as stimulators of sGC, are useful in the prevention and/ortreatment of the following types of diseases, conditions and disorderswhich can benefit from sGC stimulation:

(1) Peripheral, pulmonary, hepatic, liver, cardiac or cerebralvascular/endothelial disorders/conditions:

disorders related to high blood pressure and decreased coronary bloodflow such as increased acute and chronic coronary blood pressure,arterial hypertension and vascular disorder resulting from cardiac andrenal complications (e.g. heart disease, stroke, cerebral ischemia,renal failure); resistant hypertension, diabetic hypertension,congestive heart failure; diastolic or sistolic dysfunction; coronaryinsufficiency; arrhythmias.

thromboembolic disorders and ischemias such as myocardial infarction,stroke, transient ischemic attacks (TIAs); stable or unstable anginapectoris;

peripheral arterial disease, peripheral occlusive arterial disease;

pulmonary/respiratory conditions such as pulmonary hypertension,pulmonary arterial hypertension, and associated pulmonary vascularremodeling (e.g. localized thrombosis and right heart hypertrophy);pulmonary hypertonia; primary pulmonary hypertension, secondarypulmonary hypertension, familial pulmonary hypertension, sporadicpulmonary hypertension, pre-capillary pulmonary hypertension, idiopathicpulmonary hypertension, thrombotic pulmonary arteriopathy, plexogenicpulmonary arteriopathy;

pulmonary hypertension associated with or related to: left ventriculardysfunction, hypoxemia, mitral valve disease, constrictive pericarditis,aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonaryfibrosis, anomalous pulmonary venous drainage, pulmonary venooclusivedisease, pulmonary vasculitis, collagen vascular disease, congenitalheart disease, pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, sleep apnea, alveolar hypoventilationdisorders, chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorders, chronic thromboembolism, pulmonary embolism (due to tumor,parasites or foreign material), connective tissue disease, lupus,schitosomiasis, sarcoidosis, chronic obstructive pulmonary disease,asthma, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis and compressedpulmonary vessels (such as due to adenopathy, tumor or fibrosingmediastinitis);

arterosclerotic diseases or conditions such as atherosclerosis (e.g.,associated with endothelial injury, platelet and monocyte adhesion andaggregation, smooth muscle proliferation and migration); restenosis(e.g. developed after thrombolysis therapies, percutaneous transluminalangioplasties (PTAs), percutaneous transluminal coronary angioplasties(PTCAs) and bypass); inflammation;

cardiovascular disease associated with metabolic syndrome (e.g.,obesity, dyslipidemia, diabetis, high blood pressure); lipid relateddisorders such as dyslipidemia, hypercholesterolemia,hypertriglyceridemia, sitosterolemia, fatty liver disease, andhepatitis;

liver cirrhosis, associated with chronic liver disease, hepaticfibrosis, hepatic stellate cell activation, hepatic fibrous collagen andtotal collagen accumulation; liver disease of necro-inflammatory and/orof immunological origin; andurogenital system disorders, such as renalfibrosis and renal failure resulting from chronic kidney diseases orinsufficiency (e.g. due to accumulation/deposition and tissue injury,progressive sclerosis, glomerunephritis); prostate hypertrophy;

(2) sexual disorders of conditions: erectile dysfunction; female sexualdysfunction (e.g., female sexual arousal dysfunction), vaginal atrophyand incontinence.

In other embodiments of the invention, the compounds of Formula I aswell as pharmaceutically acceptable salts thereof are useful in theprevention and/or treatment of the following types of diseases,conditions and disorders which can benefit from sGC stimulation:hypertension, resistant hypertension, diabetic hypertension, pulmonaryhypertension (PH), pulmonary arterial hypertension, PH associated withCOPD, chronic airflow obstruction, asthma or pulmonary fibrosis,thrombosis, embolism, thromboembolic disorders, atherosclerosis, rightheart hypertrophy, heart failure, diastolic dysfunction, systolicdysfunction, sleep apnea associated with heart failure, liver cirrhosis,renal fibrosis, renal failure resulting from chronic kidney diseases orinsufficiency, metabolic disorder, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, sitosterolemia, fatty liver disease, hepatitis,erectile dysfunction, female sexual dysfunction, female sexual arousaldysfunction and vaginal atrophy.

The terms, “disease”, “disorder” and “condition” may be usedinterchangeably here to refer to an sGC, cGMP and/or NO mediated medicalor pathological condition.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),specifically a “mammal” including a non-primate (e.g., a cow, pig,horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and aprimate (e.g., a monkey, chimpanzee and a human), and more specificallya human. In some embodiments, the subject is a non-human animal such asa farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog,cat, guinea pig or rabbit). In some embodiments, the subject is a human.

The invention also provides a method for treating one of the abovediseases, conditions and disorders in a subject, comprisingadministering a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, to the subjectin need of the treatment. Alternatively, the invention provides the useof a compound of Formula I, or a pharmaceutically acceptable saltthereof, in the treatment of one of these diseases, conditions anddisorders in a subject in need of the treatment. The invention furtherprovides a method of making or manufacturing a medicament useful fortreating one of these diseases, conditions and disorders comprisingusing a compound of Formula I, or a pharmaceutically acceptable saltthereof.

The term “biological sample”, as used herein, refers to an in vitro orex vivo sample, and includes, without limitation, cell cultures orextracts thereof; biopsied material obtained from a mammal or extractsthereof; blood, saliva, urine, faeces, semen, tears, lymphatic fluid,ocular fluid, vitreous humour, or other body fluids or extracts thereof.

“Treat”, “treating” or “treatment” with regard to a disorder or diseaserefers to alleviating or abrogating the cause and/or the effects of thedisorder or disease. As used herein, the terms “treat”, “treatment” and“treating” refer to the reduction or amelioration of the progression,severity and/or duration of an sGC, cGMP and/or NO mediated condition,or the amelioration of one or more symptoms (preferably, one or morediscernable symptoms) of said condition (i.e. “managing” without“curing” the condition), resulting from the administration of one ormore therapies (e.g., one or more therapeutic agents such as a compoundor composition of the invention). In specific embodiments, the terms“treat”; “treatment” and “treating” refer to the amelioration of atleast one measurable physical parameter of an sGC, cGMP and/or NOmediated condition. In other embodiments the terms “treat”, “treatment”and “treating” refer to the inhibition of the progression of an sGC,cGMP and/or NO mediated condition, either physically by, e.g.,stabilization of a discernable symptom or physiologically by, e.g.,stabilization of a physical parameter, or both.

The term “preventing” as used herein refers to administering amedicament beforehand to avert or forestall the appearance of one ormore symptoms of a disease or disorder. The person of ordinary skill inthe medical art recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, or symptom of the condition and this is thesense intended in this disclosure. The Physician's Desk Reference, astandard text in the field, uses the term “prevent” hundreds of times.As used therein, the terms “prevent”, “preventing” and “prevention” withregard to a disorder or disease, refer to averting the cause, effects,symptoms or progression of a disease or disorder prior to the disease ordisorder fully manifesting itself

In one embodiment, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, having apredisposition (e.g. a genetic predisposition) to developing an sGC,cGMP and/or NO related disease, disorder or symptom.

In other embodiments, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, suffering froma disease, disorder or condition that makes him at risk of developing ansGC, cGMP or NO related disease, disorder or symptom.

The compounds and pharmaceutical compositions described herein can beused alone or in combination therapy for the treatment or prevention ofa disease or disorder mediated, regulated or influenced by sGC, cGMPand/or NO.

Compounds and compositions here disclosed are also useful for veterinarytreatment of companion animals, exotic animals and farm animals,including, without limitation, dogs, cats, mice, rats, hamsters,gerbils, guinea pigs, rabbits, horses, pigs and cattle.

In other embodiments, the invention provides a method of stimulating sGCactivity in a biological sample, comprising contacting said biologicalsample with a compound or composition of the invention. Use of a sGCstimulator in a biological sample is useful for a variety of purposesknown to one of skill in the art. Examples of such purposes include,without limitation, biological assays and biological specimen storage.

Combination Therapies

The compounds and pharmaceutical compositions described herein can beused in combination therapy with one or more additional therapeuticagents. For combination treatment with more than one active agent, wherethe active agents are in separate dosage formulations, the active agentsmay be administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

When co-administered with other agents, e.g., when co-administered withanother pain medication, an “effective amount” of the second agent willdepend on the type of drug used. Suitable dosages are known for approvedagents and can be adjusted by the skilled artisan according to thecondition of the subject, the type of condition(s) being treated and theamount of a compound described herein being used. In cases where noamount is expressly noted, an effective amount should be assumed. Forexample, compounds described herein can be administered to a subject ina dosage range from between about 0.01 to about 10,000 mg/kg bodyweight/day, about 0.01 to about 5000 mg/kg body weight/day, about 0.01to about 3000 mg/kg body weight/day, about 0.01 to about 1000 mg/kg bodyweight/day, about 0.01 to about 500 mg/kg body weight/day, about 0.01 toabout 300 mg/kg body weight/day, about 0.01 to about 100 mg/kg bodyweight/day.

When “combination therapy” is employed, an effective amount can beachieved using a first amount of a compound of Formula I or apharmaceutically acceptable salt thereof and a second amount of anadditional suitable therapeutic agent.

In one embodiment of this invention, a compound of Formula I and theadditional therapeutic agent are each administered in an effectiveamount (i.e., each in an amount which would be therapeutically effectiveif administered alone). In another embodiment, the compound of Formula Iand the additional therapeutic agent are each administered in an amountwhich alone does not provide a therapeutic effect (a sub-therapeuticdose). In yet another embodiment, the compound of Formula I can beadministered in an effective amount, while the additional therapeuticagent is administered in a sub-therapeutic dose. In still anotherembodiment, the compound of Formula I can be administered in asub-therapeutic dose, while the additional therapeutic agent, forexample, a suitable cancer-therapeutic agent is administered in aneffective amount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a subject.

Co-administration encompasses administration of the first and secondamounts of the compounds in an essentially simultaneous manner, such asin a single pharmaceutical composition, for example, capsule or tablethaving a fixed ratio of first and second amounts, or in multiple,separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequentialmanner in either order. When co-administration involves the separateadministration of the first amount of a compound of Formula I and asecond amount of an additional therapeutic agent, the compounds areadministered sufficiently close in time to have the desired therapeuticeffect. For example, the period of time between each administrationwhich can result in the desired therapeutic effect, can range fromminutes to hours and can be determined taking into account theproperties of each compound such as potency, solubility,bioavailability, plasma half-life and kinetic profile. For example, acompound of Formula I and the second therapeutic agent can beadministered in any order within about 24 hours of each other, withinabout 16 hours of each other, within about 8 hours of each other, withinabout 4 hours of each other, within about 1 hour of each other or withinabout 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeuticagent such as a compound described herein) can be administered prior to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksbefore), concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapy (e.g., a prophylactic or therapeuticagent such as an anti-cancer agent) to a subject.

Examples of other therapeutic agents that may be combined with acompound of this disclosure, either administered separately or in thesame pharmaceutical composition, include, but are not limited to:

(1) Endothelium-derived releasing factor (EDRF);(2) NO donors such as a nitrosothiol, a nitrite, a sydnonimine, aNONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a nitrosimine,nitrotyrosine, a diazetine dioxide, an oxatriazole 5-imine, an oxime, ahydroxylamine, a N-hydroxyguanidine, a hydroxyurea or a furoxan. Someexamples of these types of compounds include: glyceryl trinitrate (alsoknown as GTN, nitroglycerin, nitroglycerine, and trinitrogylcerin), thenitrate ester of glycerol; sodium nitroprusside (SNP), wherein amolecule of nitric oxide is coordinated to iron metal forming a squarebipyramidal complex; 3-morpholinosydnonimine (SIN-1), a zwitterioniccompound formed by combination of a morpholine and a sydnonimine;S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acidderivative with a nitrosothiol functional group; diethylenetriamine/NO(DETA/NO), a compound of nitric oxide covalently linked todiethylenetriamine; and NCX 4016, an m-nitroxymethyl phenyl ester ofacetyl salicylic acid. More specific examples of some of these classesof NO donors include: the classic nitrovasodilators, such as organicnitrate and nitrite esters, including nitroglycerin, amyl nitrite,isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil;Isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Isordil®,Titradose®, Monoket®), FK 409 (NOR-3); FR 144420 (NOR-4);3-morpholinosydnonimine; Linsidomine chlorohydrate (“SIN-1”);S-nitroso-N-acetylpenicillamine (“SNAP”); AZD3582 (CINOD lead compound),NCX 4016, NCX 701, NCX 1022, HCT 1026, NCX 1015, NCX 950, NCX 1000, NCX1020, AZD 4717, NCX 1510/NCX 1512, NCX 2216, and NCX 4040 (all availablefrom NicOx S.A.), S-nitrosoglutathione (GSNO), Sodium Nitroprusside,S-nitrosoglutathione mono-ethyl-ester (GSNO-ester),6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexanamine (NOC-9) ordiethylamine NONOate. Nitric oxide donors are also as disclosed in U.S.Pat. Nos. 5,155,137, 5,366,997, 5,405,919, 5,650,442, 5,700,830,5,632,981, 6,290,981, 5,691,423 5,721,365, 5,714,511, 6,511,911, and5,814,666, Chrysselis et al. (2002) J Med Chem. 45:5406-9 (such as NOdonors 14 and 17), and Nitric Oxide Donors for Pharmaceutical andBiological Research, Eds: Peng George Wang, Tingwei Bill Cai, NaoyukiTaniguchi, Wiley, 2005;(3) Other substances that enhance cGMP concentrations such asprotoporphyrin IX, arachidonic acid and phenyl hydrazine derivatives;(4) Nitric Oxide Synthase substrates: for example, n-hydroxyguanidinebased analogs, such as N[G]-hydroxy-L-arginine (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine, and PR5 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine); L-argininederivatives (such as homo-Arg, homo-NOHA, N-tert-butyloxy- andN-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilonguanidine-carpoic acid, agmatine, hydroxyl-agmatine, andL-tyrosyl-L-arginine); N-alkyl-N′-hydroxyguanidines (such asN-cyclopropyl-N′-hydroxyguanidine and N-butyl-N′-hydroxyguanidine),N-aryl-N′-hydroxyguanidines (such as N-phenyl-N′-hydroxyguanidine andits para-substituted derivatives which bear —F, —Cl, -methyl, —OHsubstituents, respectively); guanidine derivatives such as3-(trifluormethyl) propylguanidine; and others reviewed in Cali et al.(2005, Current Topics in Medicinal Chemistry 5:721-736) and disclosed inthe references cited therein;(5) Compounds which enhance eNOS transcription: for example thosedescribed in WO 02/064146, WO 02/064545, WO 02/064546 and WO 02/064565,and corresponding patent documents such as US2003/0008915,US2003/0022935, US2003/0022939 and US2003/0055093. Other eNOStranscriptional enhancers including those described in US20050101599(e.g. 2,2-difluorobenzo[1,3]dioxol-5-carboxylic acid indan-2-ylamide,and 4-fluoro-N-(indan-2-yl)-benzamide), and Sanofi-Aventis compoundsAVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schäfer et al.,Journal of Thrombosis and Homeostasis 2005; Volume 3, Supplement 1:abstract number P1487);(6) NO independent heme-independent sGC activators, including, but notlimited to: BAY 58-2667 (see patent publication DE19943635)

HMR-1766 (ataciguat sodium, see patent publication WO2000002851)

S 3448(2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide(see patent publications DE19830430 and WO2000002851)

and HMR-1069 (Sanofi-Aventis).

(7) Heme-dependent sGC stimulators including, but not limited to:

YC-1 (see patent publications EP667345 and DE19744026)

BAY 41-2272 (see patent publications DE19834047 and DE19942809)

BAY 41-8543 (see patent publication DE19834044)

BAY 63-2521 (see patent publication DE19834044)

CFM-1571 (see patent publication WO2000027394)

and other compounds disclosed in Tetrahedron Letters (2003), 44(48):8661-8663.(8) Compounds that inhibit the degradation of cGMP, such as:PDE5 inhibitors, such as, for example, Sildenafil (Viagra®) and otherrelated agents such as Avanafil, Lodenafil, Mirodenafil, Sildenafilcitrate (Revatio®), Tadalafil (Cialis® or Adcirca®), Vardenafil(Levitra) and Udenafil; Alprostadil; and Dipyridamole;(9) Calcium channel blockers such as:Dihydropyridine calcium channel blockers: Amlodipine (Norvasc),Aranidipine (Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa),Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard),Clevidipine (Cleviprex), Diltiazem, Efonidipine (Landel), Felodipine(Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip),Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR),Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine(Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif,Nitrepin, Baylotensin), Pranidipine (Acalas), Isradipine (Lomir);Phenylalkylamine calcium channel blockers: Verapamil (Calan, Isoptin)

Gallopamil (Procorum, D600); Benzothiazepines: Diltiazem (Cardizem);

Nonselective calcium channel inhibitors such as: mibefradil, bepridiland fluspirilene, fendiline;(10) Endothelin receptor antagonists (ERAs): for instance the dual (ETAand ETB) endothelin receptor antagonist Bosentan (marketed asTracleer®); Sitaxentan, marketed under the name Thelin®; Ambrisentan ismarketed as Letairis® in U.S.; dual/nonselective endothelin antagonistActelion-1, that entered clinical trials in 2008;(11) Prostacyclin derivatives or analogues: for instance prostacyclin(prostaglandin 12), Epoprostenol (synthetic prostacyclin, marketed asFlolan®); Treprostinil (Remodulin®), Iloprost (Ilomedin®), Iloprost(marketed as Ventavis®); oral and inhaled forms of Remodulin® that areunder development; Beraprost, an oral prostanoid available in Japan andSouth Korea;(12) Antihyperlipidemics such as: bile acid sequestrants (e.g.,Cholestyramine, Colestipol, Colestilan and Colesevelam); statins such asAtorvastatin, Simvastatin, Lovastatin, Fluvastatin, Pitavastatin,Rosuvastatin and Pravastatin; cholesterol absorption inhibitors such asEzetimibe; other lipid lowering agents such as Icosapent ethyl ester,Omega-3-acid ethyl esters, Reducol; fibric acid derivatives such asClofibrate, Bezafibrate, Clinofibrate, Gemfibrozil, Ronifibrate,Binifibrate, Fenofirate, Ciprofibrate, Choline fenofibrate; nicotinicacid derivatives such as Acipimox and Niacin; also combinations ofstatins, niacin, intestinal cholesterol absorption-inhibitingsupplements (ezetimibe and others) and fibrates; antiplatelet therapiessuch as Clopidogrel bisulfate;(13) Anticoagulants, such as the following types:

Coumarines (Vitamin K antagonists): Warfarin® (Coumadin) mostly used inthe US and UK; Acenocoumarol® and Phenprocoumon®, mainly used in othercountries; Phenindione®;

Heparin and derivative substances such as: Heparin; low molecular weightheparin, Fondaparinux and Idraparinux;

Direct thrombin inhibitors such as: Argatroban, Lepirudin, Bivalirudinand Dabigatran; Ximelagatran (Exanta®), not approved in the US;

Tissue plasminogen activators, used to dissolve clots and unblockarteries, such as Alteplase;

(14) Antiplatelet drugs: for instance thienopyridines such as Lopidogreland Ticlopidine; Dipyridamole; Aspirin;(15) ACE inhibitors, for example the following types:

Sulfhydryl-containing agents such as Captopril (trade name Capoten®),the first ACE inhibitor and Zofenopril;

Dicarboxylate-containing agents such as Enalapril (Vasotec/Renitec®);Ramipril (Altace/Tritace/Ramace/Ramiwin®); Quinapril (Accupril®),Perindopril (Coversyl/Aceon®); Lisinopril (Lisodur/Lopril/Novatec/Prinivil/Zestril®) and Benazepril (Lotensin®);

Phosphonate-containing agents such as: Fosinopril;

Naturally occurring ACE inhibitors such as: Casokinins and lactokinins,which are breakdown products of casein and whey that occur naturallyafter ingestion of milk products, especially cultured milk; TheLactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probioticLactobacillus helveticus or derived from casein also have ACE-inhibitingand antihypertensive functions;

Other ACE inhibitors such as Alacepril, Delapril, Cilazapril, Imidapril,Trandolapril, Temocapril, Moexipril, Spirapril,

(16) Supplemental oxygen therapy;(17) Beta blockers, such as the following types:

Non-selective agents: Alprenolol®, Bucindolol®, Carteolol®, Carvedilol®(has additional α-blocking activity), Labetalol® (has additionalα-blocking activity), Nadolol®, Penbutolol® (has intrinsicsympathomimetic activity), Pindolol® (has intrinsic sympathomimeticactivity), Oxprenonol, Acebutolol, Sotalol, Mepindolol, Celiprolol,Arotinolol, Tertatolol, Amosulalol, Nipradilol, Propranolol® andTimolol®;

β₁-Selective agents: Acebutolol® (has intrinsic sympathomimeticactivity), Atenolol®, Betaxolol®, Bisoprolol®, Celiprolol®, Dobutaminehydrochloride, Irsogladine maleate, Carvedilol, Talinolol, Esmolol®,Metoprolol® and Nebivolol®;

β₂-Selective agents: Butaxamine® (weak α-adrenergic agonist activity);

(18) Antiarrhythmic agents such as the following types:

Type I (sodium channel blockers): Quinidine, Lidocaine, Phenytoin,Propafenone

Type III (potassium channel blockers): Amiodarone, Dofetilide, Sotalol

Type V: Adenosine, Digoxin

(19) Diuretics such as: Thiazide diuretics, e.g., Chlorothiazide,Chlorthalidone, and Hydrochlorothiazide, Bendroflumethiazide,Cyclopenthiazide, Methyclothiazide, Polythiazide, Quinethazone,Xipamide, Metolazone, Indapamide, Cicletanine; Loop diuretics, such asFurosemide and Toresamide; potassium-sparing diuretics such asAmiloride, Spironolactone, Canrenoate potassium, Eplerenone andTriamterene; combinations of these agents; other diuretics such asAcetazolamid and Carperitide(20a) Direct acting vasodilators such as Hydralazine hydrochloride,Diazoxide, Sodium nitroprusside, Cadralazine; other vasodilators such asIsosorbide dinitrate and Isosorbide 5-mononitrate;(20b) Exogenous vasodilators such as:

Adenocard®, an adenosine agonist, primarily used as an antiarrhythmic;

Alpha blockers (which block the vasoconstricting effect of adrenaline):Alpha-1-adrenoceptor antagonists such as Prazosin, Indoramin, Urapidil,Bunazosin, Terazosin, Doxazosin

Atrial natriuretic peptide (ANP);

Ethanol;

Histamine-inducers, which complement proteins C3a, C4a and C5a work bytriggering histamine release from mast cells and basophil granulocytes;

Tetrahydrocannabinol (THC), major active chemical in marijuana which hasminor vasodilatory effects;

Papaverine, an alkaloid found in the opium poppy papaver somniferum;b

(21) Bronchodilators: there are two major types of bronchodilator, β₂agonists and anticholinergics, exemplified below:

β₂ agonists: Salbutamol® or albuterol (common brand name: Ventolin) andTerbutaline® are short acting β₂ agonists for rapid relief of COPDsymptoms. Long acting β₂ agonists (LABAs) such as Salmeterol® andFormoterol®;

anticholinergics: Ipratropium® is the most widely prescribed shortacting anticholinergic drug. Tiotropium® is the most commonly prescribedlong-acting anticholinergic drug in COPD;

Theophylline®, a bronchodilator and phosphodiesterase inhibitor;

(22) Corticosteroids: such as beclomethasone, methylprednisolone,betamethasone, prednisone, prenisolone, triamcinolone, dexamethasone,fluticasone, flunisolide and hydrocortisone, and corticosteroid analogssuch as budesonide(23) Dietary supplements such as, for example: omega-3 oils; folid acid,niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark,Tribulus terrestris, arginine, Avena sativa, horny goat weed, maca root,muira puama, saw palmetto, and Swedish flower pollen; Vitamin C, VitaminE, Vitamin K2; Testosterone supplements, Testosterone transdermal patch;Zoraxel, Naltrexone, Bremelanotide (formerly PT-141), Melanotan II,hMaxi-K; Prelox: a Proprietary mix/combination of naturally occurringingredients, L-arginine aspartate and Pycnogenol;(24) PGD2 receptor antagonists including, but not limited to, compoundsdescribed as having PGD2 antagonizing activity in United StatesPublished Applications US20020022218, US20010051624, and US20030055077,PCT Published Applications WO9700853, WO9825919, WO03066046, WO03066047,WO03101961, WO03101981, WO04007451, WO0178697, WO04032848, WO03097042,WO03097598, WO03022814, WO03022813, and WO04058164, European PatentApplications EP945450 and EP944614, and those listed in: Torisu et al.2004 Bioorg Med Chem Lett 14:4557, Torisu et al. 2004 Bioorg Med ChemLett 2004 14:4891, and Torisu et al. 2004 Bioorg & Med Chem 200412:4685;(25) Immunosuppressants such as cyclosporine (cyclosporine A,Sandimmune® Neoral®), tacrolimus (FK-506, Prograf®), rapamycin(sirolimus, Rapamune®) and other FK-506 type immunosuppressants, andmycophenolate, e.g., mycophenolate mofetil (CellCept®);(26) Non-steroidal anti-asthmatics such as β2-agonists (e.g.,terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,salmeterol, bitolterol and pirbuterol) and β2-agonist-corticosteroidcombinations (e.g., salmeterol-fluticasone (Advair®),formoterol-budesonid (Symbicort®)), theophylline, cromolyn, cromolynsodium, nedocromil, atropine, ipratropium, ipratropium bromide,leukotriene biosynthesis inhibitors (zileuton, BAY1005);(27) Non-steroidal anti-inflammatory agents (NSAIDs) such as propionicacid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acidderivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetyl salicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone);(28) Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®),rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib;(opioid analgesics such as codeine, fentanyl, hydromorphone,levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone,propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine andpentazocine; and(29) Anti-diabetic agents such as insulin and insulin mimetics,sulfonylureas (e.g., Glyburide, Glybenclamide, Glipizide, Gliclazide,Gliquidone, Glimepiride, Meglinatide, Tolbutamide, Chlorpropamide,Acetohexamide, Tolazamide), biguanides, e.g., metformin (Glucophage®),α-glucosidase inhibitors (such as Acarbose, Epalrestat, Voglibose,Miglitol), thiazolidinone compounds, e.g., rosiglitazone (Avandia®),troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) andenglitazone; insulin sensitizers such as Pioglitazone and Rosiglitazone;Insulin secretagogues such as Repaglinide, Nateglinide and Mitiglinide;Incretin mimetics such as Exanatide and Liraglutide; Amylin analoguessuch as Pramlintide; glucose lowering agents such as Chromiummpicolinate (optinally combined with biotin); dipeptidyl peptidase IVinhibitors such as Sitagliptin, Vildagliptin, Saxagliptin, Alogliptinand Linagliptin; vaccines currently being developed for the treatment ofdiabetes; AVE-0277, Alum-GAD, BHT-3021, IBC-VS01; cytokine targetedtherapies in development for the treatment of diabetes such as Anakinra,Canakinumab, Diacerein, Gevokizumab, LY-2189102, MABP-1, GIT-027; drugsin development for the treatment of diabetes:

Drugs in development for the treatment of diabetes Mechanism of DrugName Organization Action Status Dapagliflozin AstraZeneca/Bristol-SGLT-2 Inhibitors Recommended Myers Squibb Approval Alogliptin TakedaInsulin Sensitizers/ Pre-Registered benzoate/metformin DipeptidylPeptidase hydrochloride IV (CD26; DPP-IV; DP-IV) Inhibitors AnagliptinKowa/Sanwa Dipeptidyl Peptidase Pre-Registered IV (CD26; DPP-IV; DP-IV)Inhibitors Insulin degludec Novo Nordisk Pre-Registered Insulindegludec/insulin Novo Nordisk Pre-Registered aspart Insulin human (rDNAMannKind Pre-Registered origin) inhalation powder Lixisenatide SanofiInsulin Pre-Registered Secretagogues/GLP- 1 Receptor AgonistsRecombinant human Biodel Pre-Registered insulin Teneligliptin MitsubishiTanabe Dipeptidyl Peptidase Pre-Registered Pharma IV (CD26; DPP-IV;DP-IV) Inhibitors AVE-0277 Andromeda Biotech/ Phase III Teva AlbiglutideGlaxoSmithKline GLP-1 Receptor Phase III Agonists Aleglitazar RochePPARalpha Agonists/ Phase III PPARgamma Agonists AtorvastatinGlaxoSmithKline K(ATP) Channel Phase III calcium/glimepirideBlockers/Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV)Inhibitors/HMG-CoA Reductase Inhibitors/ TNFSF6 Expression InhibitorsBYK-324677 Nycomed Phase III Balaglitazone Dr. Reddy's InsulinSensitizers/ Phase III Laboratories PPARgamma Partial Agonists CSG-452Chugai SGLT-2 Inhibitors Phase III Pharmaceutical Canagliflozin Johnson& Johnson/ SGLT-2 Inhibitors Phase III Mitsubishi Tanabe PharmaCanagliflozin/metformin Johnson & Johnson SGLT-2 Inhibitors/ Phase IIIhydrochloride Insulin Sensitizers Dapagliflozin/MetforminAstraZeneca/Bristol- SGLT-2 Inhibitors/ Phase III hydrochloride MyersSquibb Insulin Sensitizers Dulaglutide Lilly Insulin Phase IIISecretagogues/GLP- 1 Receptor Agonists Empagliflozin BoehringerIngelheim/ SGLT-2 Inhibitors Phase III Lilly Empagliflozin/linagliptinBoehringer Ingelheim/ SGLT-2 Inhibitors/ Phase III Lilly DipeptidylPeptidase IV (CD26; DPP-IV; DP-IV) Inhibitors Gemigliptin LG LifeSciences Dipeptidyl Peptidase Phase III IV (CD26; DPP-IV; DP-IV)Inhibitors Hepatic-directed vesicle Diasome Phase III insulinPharmaceuticals Human isophane insulin Wockhardt Phase III IN-105 BioconPhase III Insulin Novo Nordisk Insulin Phase III degludec/liraglutideSecretagogues/GLP- 1 Receptor Agonists Insulin glargine Sanofi Phase IIIIpragliflozin L-proline Astellas Pharma/ SGLT-2 Inhibitors Phase IIIKotobuki LY-2605541 Lilly Phase III LY-2963016 Lilly Phase IIILixisenatide/Insulin Sanofi Insulin Phase III Secretagogues/GLP-glargine 1 Receptor Agonists Lobeglitazone sulfate Chong Kun DangPPARalpha Agonists/ Phase III Pharm (CKD Pharm) PPARgammaAgonists/Insulin Sensitizers Luseogliflozin Taisho SGLT-2 InhibitorsPhase III Otelixizumab Tolerx Anti-CD3 Phase III Ranolazine GileadSodium Channel Phase III Blockers Recombinant human National Instituteof Phase III insulin Health Sciences Sitagliptin phosphate Merck & Co.PPARgamma Phase III monohydrate/pioglitazone Agonists/Insulinhydrochloride Sensitizers/ Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV)Inhibitors Sitagliptin/atorvastatin Merck & Co. Dipeptidyl PeptidasePhase III calcium IV (CD26; DPP-IV; DP-IV) Inhibitors/ HMG-CoA ReductaseInhibitors/TNFSF6 Expression Inhibitors TAK-875 Takeda Free Fatty AcidPhase III Receptor 1 (FFAR1; GPR40) Agonists/ Insulin SecretagoguesTT-401 7TM Pharma Cannabinoid CB1 Phase I Antagonists TT-401 TransitionPhase I Therapeutics ZYH-2 Cadila Healthcare PPARalpha Ligands/ Phase I(d/b/a Zydus Cadila) PPARgamma Ligands ZYO-1 Cadila HealthcareCannabinoid CB1 Phase I (d/b/a Zydus Cadila) Antagonists 701645 CellonisPhase I Biotechnologies 701499 Cellonis Phase I Biotechnologies 743300University of Phase I California, San Francisco 448661 University ofPhase I Pittsburgh AD-1 National Institute Clinical Pharma Res DevColesevelam Daiichi Sankyo Bile Acid Clinical hydrochloride SequestrantsDBPR-108 National Health IND Filed Research Institutes/ ScinoPharmNodlin Biolaxy IND Filed PSN-491 Prosidion Glucose-Dependent IND FiledInsulinotropic Receptor (GDIR, GPR119) Agonists/ Dipeptidyl Peptidase IV(CD26; DPP-IV; DP-IV) Inhibitors Tolimidone Melior Discovery Lyn KinaseActivators IND Filed ZYD-1 Cadila Healthcare GLP-1 Receptor IND Filed(d/b/a Zydus Cadila) Agonists ZYOG-1 Cadila Healthcare GLP-1 ReceptorIND Filed (d/b/a Zydus Cadila) Agonists(30) HDL cholesterol-increasing agents such as Anacetrapib, MK-524A,CER-001, DRL-17822, Dalcetrapib, JTT-302, RVX-000222, TA-8995;(31) Antiobesity drugs such as Methamphetamine hydrochloride,Amfepramone hydrochloride (Tenuate®), Phentermine (Ionamin®),Benzfetamine hydrochloride (Didrex®), Phendimetrazine tartrate(Bontril®, Prelu-2®, Plegine®), Mazindol (Sanorex®), Orli stat(Xenical®), Sibutramine hydrochloride monohydrate (Meridia®, Reductil®),Rimonabant (Acomplia®), Amfepramone, Chromium picolinate, RM-493,TZP-301; combination such as Phentermine/Topiramate,Bupropion/Naltrexone, Sibutramine/Metformin, Bupropion SR/Zonisamide SR,Salmeterol, xinafoate/fluticasone propionate; Lorcaserin hydrochloride,Phentermine/topiramate, Bupropion/naltrexone, Cetilistat, Exenatide,KI-0803, Liraglutide, Metformin hydrochloride, Sibutramine/Metformin,876167, ALS-L-1023, Bupropion SR/Zonisamide SR, CORT-108297,Canagliflozin, Chromium picolinate, GSK-1521498, LY-377604, Metreleptin,Obinepitide, P-57AS3, PSN-821, Salmeterol xinafoate/fluticasonepropionate, Sodium tungstate, Somatropin (recombinant), TM-30339,TTP-435, Tesamorelin, Tesofensine, Velneperit, Zonisamide, BMS-830216,ALB-127158, AP-1030, ATHX-105, AZD-2820, AZD-8329, Beloranibhemioxalate, CP-404, HPP-404, ISIS-FGFR4Rx, Insulinotropin, KD-3010PF,05212389, PP-1420, PSN-842, Peptide YY3-36, Resveratrol, S-234462;S-234462, Sobetirome, TM-38837, Tetrahydrocannabivarin, ZYO-1,beta-Lapachone;(32) Angiotensin receptor blockers such as Losartan, Valsartan,Candesartan cilexetil, Eprosaran, Irbesartan, Telmisartan, Olmesartranmedoxomil, Azilsartan medoxomil;(33) Renin inhibitors such as Aliskiren hemifumirate;(34) Centrally acting alpha-2-adrenoceptor agonists such as Methyldopa,Clonidine, Guanfacine;(35) Adrenergic neuron blockers such as Guanethidine, Guanadrel;(36) Imidazoline I-1 receptor agonists such as Rimenidine dihydrogenphosphate and Moxonidine hydrochloride hydrate;(37) Aldosterone antagonists such as Spironolactone and Eplerenone(38) Potassium channel activators such as Pinacidil(39) Dopamine D1 agonists such as Fenoldopam mesilate; Other dopamineagonists such as Ibopamine, Dopexamine and Docarpamine;(40) 5-HT2 antagonists such as Ketanserin;(41) Drugs that are currently being developed for the treatment ofarterial hypertension:

Mechanism of Drug Name Organization Action Status Azilsartan TakedaAngiotensin AT1 Registered Antagonists/ Angiotensin AT2 Antagonists/Insulin Sensitizers Amlodipine besylate/irbesartan Dainippon SumitomoAngiotensin AT1 Pre-Registered Pharma Antag Calcium Channel BlockersAzilsartan/amlodipine besilate Takeda Angiotensin AT1 Phase IIIAntagonists/ Insulin Sensitizers/ Calcium Channel BlockersCilnidipine/valsartan Ajinomoto/Mochida Angiotensin AT1 Phase IIIAntagonists/ Calcium Channel Blockers Fimasartan Boryung Angiotensin AT1Phase III Antagonists Irbesartan/atorvastatin Hanmi Angiotensin AT1Phase III Antagonists/ Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV)Inhibitors/HMG- CoA Reductase Inhibitors/ TNFSF6 Expression InhibitorsIrbesartan/trichlormethiazide Shionogi Angiotensin AT1 Phase IIIAntagonists Losartan Merck & Co. Angiotensin AT1 Phase IIIpotassium/hydrochlorothiazide/am Antagonists/ lodipine besylate CalciumChannel Blockers Pratosartan Boryung Angiotensin AT1 Phase IIIAntagonists ACT-280778 Actelion Phase II Amiloride HemodynamicMineralocorticoid Phase II hydrochloride/spironolactone TherapeuticsReceptor (MR) Antagonists/ Na+/H+ Exchanger (NHE) Inhibitors/ EpithelialSodium Channels (ENaC) Blockers/ K(V)1.5 Channel Blockers/ K(V)4.3Channel Blockers Angiotensin vaccine/CoVaccine HT BTG Phase IICYT006-AngQb Cytos Biotechnology Anti-Angiotensin Phase II IICholecalciferol Emory University Phase II Cobiprostone Sucampo CIC-2Channel Phase II Pharmaceuticals Activators INT-001 IntelGenx Phase IILCZ-696 Novartis Angiotensin AT1 Phase II Antagonists/ Neprilysin(Enkephalinase, Neutral Endopeptidase, NEP) Inhibitors LFF-269 NovartisPhase II Octreotide acetate Chiasma Growth Hormone Phase II ReleaseInhibitors/ Somatostatin Agonists PL-3994 Palatin Technologies AtrialNatriuretic Phase II Peptide A (NPR1; Guanylate Cyclase A) ReceptorAgonists Rostafuroxine Sigma-Tau Phase II SLx-2101 NT Life SciencesPhosphodiestera Phase II se V (PDE5A) Inhibitors TBC-3711 EncysiveEndothelin ETA Phase II Pharmaceuticals Receptor Antagonists UdenafilDong-A/Falk Pharma Phosphodiesterase Phase II V (PDE5A) InhibitorsAtorvastatin calcium/losartan HanAll BioPharma Angiotensin AT1 Phase Ipotassium Antagonists/ Dipeptidyl Peptidase IV (CD26 DPP-IV; DP-IV);Inhibitors/HMG- CoA Reductase Inhibitors/ TNFSF6 Expression InhibitorsBIA-5-1058 BIAL Dopamine beta- Phase I monooxygenase Inhibitors CS-3150Daiichi Sankyo Phase I DSP-9599 Dainippon Sumitomo Renin InhibitorsPhase I Pharma MK-1597 Actelion/Merck & Co. Renin Inhibitors Phase IMK-4618 Merck & Co. Phase I MK-5478 Merck & Co. Phase I MK-7145 Merck &Co. Phase I MK-8266 Merck & Co. Phase I MK-8457 Merck & Co. Phase IMP-157 Mitsubishi Tanabe Angiotensin AT2 Phase I Pharma Agonists MT-3995Mitsubishi Tanabe Mineralocorticoid Phase I Pharma Receptor (MR)Antagonists Mirodenafil hydrochloride SK Chemicals PhosphodiesterasePhase I V (PDE5A) Inhibitors NV-04 Novogen Antioxidants Phase INifedipine/Candesartan cilexetil Bayer Angiotensin AT1 Phase IAntagonists/ Calcium Channel Blockers/ Antioxidants QGC-001 QuantumGenomics Glutamyl Phase I Aminopeptidase (Aminopeptidase A) InhibitorsRDX-5791 Ardelyx Na+/H+ Phase I Exchanger type 3 (NHE-3) InhibitorsTAK-272 Takeda Renin Inhibitors Phase I TAK-591 Takeda Angiotensin AT2Phase I Antagonists VTP-27999 Vitae Pharmaceuticals Renin InhibitorsPhase I Vasomera PhaseBio VPAC2 (VIP2) Phase I Agonists Tylerdipinehydrochloride Sihuan Calcium Channel IND Filed Pharmaceutical Blockers(42) Vasopressin antagonists such as Tolvaptan;(43) Calcium channel sensitizers such as Levosimendan or activators suchas Nicorandil;(44) PDE-3 inhibitors such as Amrinone, Milrinone, Enoximone,Vesnarinone, Pimobendan, Olprinone;(45) Adenylate cyclase activators such as Colforsin dapropatehydrochloride;(46) Positive inotropic agents such as Digoxin and Metildigoxin;metabolic cardiotonic agents such as Ubidecarenone; brain natureticpeptides such as Nesiritide;(47) Drugs that are currently in development for the treatment of heartfailure:

Drugs in development for the treatment of heart failure Mechanism DrugName Organization of Action Status Bucindolol ARCA beta-AdrenoceptorPre- hydrochloride Antagonists Registered Aliskiren Novartis ReninInhibitors Phase III hemifumarate Ferric Vifor Phase III carboxymaltoseLCZ-696 Novartis Angiotensin AT1 Phase III Antagonists/ Neprilysin(Enkephalinase, Neutral Endopeptidase, NEP) Inhibitors Neuregulin-1Zensun Phase III Olmesartan Tohoku University Angiotensin AT1 Phase IIImedoxomil Antagonists C3BS-CQR-1 Cardio3 BioSciences Phase II/IIIMyoCell Bioheart Phase II/III Serelaxin Novartis Phase II/III AAV1/AmpliPhi Biosciences/ Phase II SERCA2a Celladon/ Mount Sinai School ofMedicine Albiglutide GlaxoSmithKline GLP-1 Receptor Phase II AgonistsAllogeneic Mesoblast Phase II mesenchymal precursor cells AlsterMACSMiltenyi Biotec Phase II BAY-94-8862 Bayer Mineralocorticoid Phase IIReceptor (MR) Antagonists COR-1 Corimmun Phase II CXL-1020 CardioxylNitric Oxide Phase II Pharmaceuticals Donors Cenderitide NileTherapeutics Guanylate Cyclase Phase II Activators EndometrialERCell/Medistem Phase II regenerative cells JNJ-39588146 Johnson &Johnson Phase II Omecamtiv Amgen/Cytokinetics Cardiac Myosin Phase IImecarbil Activators PL-3994 Palatin Technologies Atrial NatriureticPhase II Peptide A (NPR1; Guanylate Cyclase A) Receptor AgonistsRemestemcel-L Osiris Phase II TRV-120027 Trevena Angiotensin AT1 PhaseII Receptor Ligands Urocortin 2 Neurocrine CRF2 Agonists Phase IIBiosciences AAV6-CMV- Imperial College Phase I/II SERCA2a AnakinraNational Institutes of IL-1 Receptor Phase I/II Health (NIH) AntagonistsLipiCell Bioheart/Instituto de Phase I/II Medicina Regenerativa ALD-201Cytomedix/Texas Phase I Heart Institute BAY-1021189 Bayer Phase IBAY-1067197 Bayer Adenine Receptor Phase I Agonists BAY-86-8050 BayerDrugs Acting on Phase I Vasopressin (AVP) Receptors BIA-5-1058 BIALDopamine beta- Phase I monooxygenase Inhibitors CSCs University of PhaseI Louisville Calcitonin gene VasoGenix Phase I related peptide JVS-100Juventas Phase I Therapeutics MyoCell SDF-1 Bioheart Phase I MyoblastAdvanced Cell Phase I Technology (ACT) RO-1160367 Serodus 5-HT4Antagonists Phase I Recombinant Acorda/Vanderbilt Phase I human glialUniversity growth factor 2 [18F]LMI-1195 Lantheus Medical Phase IImaging 677950 Kyoto Prefectural Phase I University of Medicine(48) Drugs currently in development for the treatment of pulmonaryhypertension:

Drugs in development for the treatment of pulmonary hypertension DrugName Organization Mechanism of Action Status Imatinib Novartis BreastCancer-Resistant Protein (BCRP; Pre-Registered mesylate ABCG2)Inhibitors/Abl Kinase Inhibitors/ Angiogenesis Inhibitors/Bcr-Abl KinaseInhibitors/CSF1R (c-FMS) Inhibitors/KIT (C-KIT) Inhibitors/ApoptosisInducers/ PDGFRalpha Inhibitors/PDGFRbeta Inhibitors/Inhibitors ofSignal Transduction Pathways Treprostinil United Prostacyclin AnalogsPre-Registered diethanolamine Therapeutics GSK-1325760A GlaxoSmithKlinePhase III Macitentan Actelion Endothelin ETA Receptor Antagonists/ PhaseIII Endothelin ETB Receptor Antagonists Riociguat Bayer GuanylateCyclase Activators Phase III Selexipag Actelion/Nippon Prostanoid IPAgonists Phase III Shinyaku Udenafil Dong-A Phosphodiesterase V (PDE5A)Inhibitors Phase III L-Citrulline Nat Heart, Lung, Phase II/III andBlood Institute/ Vanderbilt University BQ-123 Brigham & Endothelin ETAReceptor Antagonists Phase II Women's Hospital Cicletanine Gilead PhaseII Fasudil Asahi Kasei Rho Kinase Inhibitors/Calcium Phase IIhydrochloride Sensitizers Nilotinib Novartis Bcr-Abl KinaseInhibitors/Apoptosis Phase II hydrochloride Inducers/Inhibitors ofSignal monohydrate Transduction Pathways PRX-08066 Clinical Data 5-HT2BAntagonists Phase II Terguride ErgoNex 5-HT2A Antagonists/5-HT2B PhaseII Pharma Antagonists/Dopamine Autoreceptor Agonists/Dopamine D2Receptor Partial Agonists/Prolactin Secretion Inhibitors TezosentanActelion Endothelin ETA Receptor Antagonists/ Phase II disodiumEndothelin ETB Receptor Antagonists Anakinra Virginia IL-1 ReceptorAntagonists Phase I/II Commonwealth University (VCU) SimvastatinImperial College HDL-Cholesterol Increasing Agents/ Phase I/II HMG-CoAReductase Inhibitors 99mTC- Montreal Heart Phase I PulmoBind Institute(MHI) APD-811 Arena Prostanoid IP Agonists Phase I Sorafenib Bayer Rafkinase B Inhibitors/Raf kinase C Phase I Inhibitors/AngiogenesisInhibitors/ Flt3 (FLK2/STK1) Inhibitors/VEGFR-1 (Flt-1) Inhibitors/KIT(C-KIT) Inhibitors/ VEGFR-2 (FLK-1/KDR) Inhibitors/VEGFR- 3 (FLT4)Inhibitors/PDGFRbeta Inhibitors/RET Inhibitors/Inhibitors of SignalTransduction Pathways Triplelastat Proteo Biotech Elastase InhibitorsPhase I 2586881 Apeiron Preclinical Biologics C-122 Corridor Caspase 3Activators/Dopamine D1 Preclinical Pharmaceuticals Antagonists/5-HT2BAntagonists/5-HT7 Dopamine D2 Antagonists/Dopamine D3Antagonists/Histamine H1 Receptor Antagonists/Caspase 9 Activators/Apoptosis Inducers PLX-I United Angiogenesis Inducers PreclinicalTherapeutics(49) Drugs in current development for the treatment of female sexualdysfunction:

Drugs in active development for the treatment of female sexualdysfunction Mechanism Drug Name Organization of Action StatusAlprostadil Apricus Phase III Biosciences/ VIVUS Prasterone EndoCeutics/HSD11B1 Phase III Monash Expression University Inhibitors TestosteroneBioSante Androgen Phase III transdermal gel Receptor AgonistsBremelanotide Palatin Melanocortin Phase II Technologies MC3 ReceptorAgonists/ Melanocortin MC4 Receptor Agonists Pill-Plus Pantarhei PhaseII Bioscience Testosterone MDTS Acrux Androgen Phase II ReceptorAgonists Estradiol/testosterone BioSante Estrogen Phase I Receptor (ER)Agonists/ Androgen Receptor Agonists LGD-2941 Ligand Selective Phase IAndrogen Receptor Modulators (SARM) Lidocaine/heparin Urigen Phase IOnabotulinumtoxinA Allergan Phase I S1P-104 S1 Biopharma IND FiledPL-6983 Palatin Preclinical Technologies S1P-401 S1 BiopharmaPreclinical(50) Drugs used for the treatment of erectile dysfunction such asAlprostadil, Aviptadil, Phentolamine mesilate, Weige, Alprostadil;(51) Drugs currently in development for the treatment of male sexualdysfunction:

Drugs in active development for the treatment of erectile dysfunctionMechanism of Drug Name Organization Action Status Fluvastatin NovartisApoptosis Phase III sodium Inducers/HMG- CoA Reductase InhibitorsLodenafil Cristalia Phosphodiesterase Phase III carbonate V (PDE5A)Inhibitors EFLA-400 Chonbuk Phase II/III National University HospitalApomorphine Vectura Dopamine D2 Phase II hydrochloride AgonistsLY-900010 Lilly Phosphodiesterase Phase II V (PDE5A) Inhibitors/Selective Androgen Receptor Modulators (SARM) Nitroglycerin FuturaMedical Phase II RX-10100 Rexahn Drugs Acting on Phase II DopaminergicTransmission/ Drugs Acting on Serotonergic Transmission YHD-1023 YuhanPhase II INT-007 IntelGenx Phase I LY-2452473 Lilly Selective Phase IAndrogen Receptor Modulators (SARM) hMaxi-K Albert Einstein Phase ICollege of Medicine/Ion Channel Innovations/ Mount Sinai School ofMedicine KH-204 KMSI Clinical CKD-533 Chong Kun Dang PhosphodiesterasePreclinical Pharm (CKD V (PDE5A) Pharm) Inhibitors MP-52 BiopharmPreclinical TGHW01AP Fabre-Kramer Dopamine D1 Preclinical Agonists/Dopamine D2 Agonists(51) Drugs in development for the treatment of sleep apnea:

Drugs in development for the treatment of sleep apnea Mechanism of DrugName Organization Action Status CX-1739 Cortex AMPA Receptor Phase IIModulators Phentermine/ VIVUS AMPA Phase II topiramate Antagonists/Kainate Antagonists/ Sodium Channel Blockers/ Carbonic Anhydrase Type IIInhibitors AVE-0118 Sanofi Potassium Phase I Channel Blockers SuvorexantMerck & Co. Orexin Receptor Phase I Antagonists COL-132 CollegiumClinical Pharmaceutical(52) Drugs currently in development for the treatment of metabolicsyndrome:

Mechanism of Drug Name Organization Action Status Antiobesity drugsunder active development for the treatment of patients with metabolicsyndrome Chromium University of Phase II picolinate Pennsylvania RM-493Ipsen Melanocortin MC4 Preclinical Receptor Agonists TZP-301 TranzymeGHS Receptor Preclinical Antagonists Antihyperlipidemic drugs underactive development for the treatment of patients with metabolic syndromeGFT-505 Genfit PPARalpha Phase II Agonists/ PPARdelta Agonists MBX-8025Metabolex PPARdelta Phase II Agonists Pitavastatin Kowa APOA1 Phase Icalcium Expression Enhancers/ HMG-CoA Reductase Inhibitors/ SPP1(Osteopontin) Expression Inhibitors CDX-085 Cardax AntioxidantsPreclinical Pharmaceuticals(53) Antiobesity drugs:

Drugs marketed for the treatment of obesity Organ- Mechanism of Year andcountry Drug Name ization Action of first launch Methamphetamine AbbottNoradrenergic, alpha- 1943 (U.S.) hydrochloride and beta- (Desoxyn)adrenoceptor agonist Amfepramone Sanofi Noradrenergic release 1959(U.S.) hydrochloride stimulant (Tenuate) Phentermine UCB Noradrenergicrelease 1959 (U.S.) (Ionamin) Celltech stimulant Benzfetamine PfizerNoradrenergic release 1960 (U.S.) hydrochloride stimulant (Didrex)Phendimetrazine Pfizer Noradrenergic release 1961 (U.S.) tartrate(Bontril, stimulant Prelu-2, Plegine) Mazindol (Sanorex) NovartisNoradrenergic 1973 (U.S.) reuptake inhibitor Orlistat (Xenical) RochePancreatic lipase 1998 inhibitor (New Zealand) Sibutramine AbbottNorepinephrine and 5- 1998 (U.S.) hydrochloride HT reuptake inhibitor(withdrawn 2010) monohydrate (Meridia, Reductil) Rimonabant SanofiCannabinoid CB1 2006 (U.K.) (Acornplia) antagonist (withdrawn 2008)

Kits

The compounds and pharmaceutical formulations described herein may becontained in a kit. The kit may include single or multiple doses of twoor more agents, each packaged or formulated individually, or single ormultiple doses of two or more agents packaged or formulated incombination. Thus, one or more agents can be present in first container,and the kit can optionally include one or more agents in a secondcontainer. The container or containers are placed within a package, andthe package can optionally include administration or dosageinstructions. A kit can include additional components such as syringesor other means for administering the agents as well as diluents or othermeans for formulation. Thus, the kits can comprise: a) a pharmaceuticalcomposition comprising a compound described herein and apharmaceutically acceptable carrier, vehicle or diluent; and b) acontainer or packaging. The kits may optionally comprise instructionsdescribing a method of using the pharmaceutical compositions in one ormore of the methods described herein (e.g. preventing or treating one ormore of the diseases and disorders described herein). The kit mayoptionally comprise a second pharmaceutical composition comprising oneor more additional agents described herein for co therapy use, apharmaceutically acceptable carrier, vehicle or diluent. Thepharmaceutical composition comprising the compound described herein andthe second pharmaceutical composition contained in the kit may beoptionally combined in the same pharmaceutical composition.

A kit includes a container or packaging for containing thepharmaceutical compositions and may also include divided containers suchas a divided bottle or a divided foil packet. The container can be, forexample a paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.It is feasible that more than one container can be used together in asingle package to market a single dosage form. For example, tablets maybe contained in a bottle which is in turn contained within a box.

An example of a kit is a so-called blister pack. Blister packs are wellknown in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of individual tabletsor capsules to be packed or may have the size and shape to accommodatemultiple tablets and/or capsules to be packed. Next, the tablets orcapsules are placed in the recesses accordingly and the sheet ofrelatively stiff material is sealed against the plastic foil at the faceof the foil which is opposite from the direction in which the recesseswere formed. As a result, the tablets or capsules are individuallysealed or collectively sealed, as desired, in the recesses between theplastic foil and the sheet. Preferably the strength of the sheet is suchthat the tablets or capsules can be removed from the blister pack bymanually applying pressure on the recesses whereby an opening is formedin the sheet at the place of the recess. The tablet or capsule can thenbe removed via said opening.

It may be desirable to provide written memory aid containing informationand/or instructions for the physician, pharmacist or subject regardingwhen the medication is to be taken. A “daily dose” can be a singletablet or capsule or several tablets or capsules to be taken on a givenday. When the kit contains separate compositions, a daily dose of one ormore compositions of the kit can consist of one tablet or capsule whilea daily dose of another or more compositions of the kit can consist ofseveral tablets or capsules. A kit can take the form of a dispenserdesigned to dispense the daily doses one at a time in the order of theirintended use. The dispenser can be equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter which indicates the number of dailydoses that have been dispensed. Another example of such a memory-aid isa battery-powered micro-chip memory coupled with a liquid crystalreadout, or audible reminder signal which, for example, reads out thedate that the last daily dose has been taken and/or reminds one when thenext dose is to be taken.

EXAMPLES

All references provided in the Examples are herein incorporated byreference. As used herein, all abbreviations, symbols and conventionsare consistent with those used in the contemporary scientificliterature. See, e.g. Janet S. Dodd, ed., The ACS Style Guide: A Manualfor Authors and Editors, 2^(nd) Ed., Washington, D.C.: American ChemicalSociety, 1997, herein incorporated in its entirety by reference.

Example 1 Syntheses of the Compounds of Table 1 General Procedure A

Step 1: Dione Enolate Formation:

To a solution of ketone A in THF cooled to −78° C., LiHMDS (e.g., 0.9eq, 1.0 M in toluene) is added dropwise, for example using a syringe.The reaction mixture is then allowed to warm to about 0° C., thencharged with diethyl oxalate (1.2 eq). At this time, the reactionmixture is warmed to room temperature and stirred at that temperatureuntil judged complete (e.g., using either TLC or LC/MS analysis). Oncethe reaction is complete (reaction time typically about 45 minutes), theproduct dione enolate B is used as-is in Step 2, i.e., the cyclizationstep, without any further purification.

Step 2: Pyrazole Formation:

Dione enolate B is diluted with ethanol and consecutively charged withHCl (e.g., 3 eq, 1.25M solution in ethanol) and arylhydrazine hydrate(e.g., 1.15 eq). The reaction mixture is heated to about 70° C. andstirred at this temperature until cyclization is deemed complete (e.g.,by LC/MS analysis, typically about 30 minutes). Once complete, thereaction mixture is treated carefully with solid sodium bicarbonate(e.g., 4 eq) and diluted with dichloromethane and water. The organiclayer is separated, and the aqueous layer is further diluted with waterbefore extraction with dichloromethane (3 times). The combined organicsare washed with brine, dried over MgSO₄, filtered, and concentrated invacuo. The resulting pyrazole C is then purified by SiO₂ chromatographyusing an appropriate gradient of EtOAc/hexanes.

Step 3: Amidine Formation:

To a suspension of NH₄Cl (e.g., 5 eq) in toluene cooled to about 0° C.is added AlMe₃ (e.g., 5 eq, 2.0M solution in toluene) dropwise, e.g.,via a syringe. The reaction mixture is allowed to warm to roomtemperature, and stirred until no more bubbling is observed. Pyrazole Cis added in 1 portion to the reaction mixture, heated to about 110° C.,and stirred at this temperature until judged complete (e.g., usingeither TLC or LC/MS analysis). Once complete, the reaction mixture iscooled, treated with excess methanol, and stirred vigorously for about 1hour at room temperature. The thick slurry is filtered, and theresulting solid cake is washed with methanol. The filtrate isconcentrated in vacuo, and the resulting solids are re-suspended in anethyl acetate:isopropyl alcohol, 5:1 v:v, solvent mixture. The reactionmixture is further treated with a saturated sodium carbonate solution,and stirred for about 10 minutes before the layers are separated. Theaqueous layer is extracted with the ethyl acetate:isopropyl alcohol, 5:1v:v, solvent mixture (3×), and the combined organics are washed withbrine. The organics are further dried over MgSO4, filtered, and thesolvent is removed in vacuo. The product amidine D is used as-is insubsequent steps without further purification.

Preparation of Compound I-2

Intermediate D-1 was accessed via General Procedure A in 58% yield from1-(isoxazol-3-yl)ethanone using (thiophen-3-ylmethyl)hydrazinehydrochloride in the second step. Intermediate D1: ¹H-NMR (400 MHz,DMSO-d₆) δ 9.23-9.16 (m, 1H), 8.76 (br s, 3H), 7.73-7.81 (m, 1H), 7.49(dt, 1H), 7.31 (br s, 1H), 7.08-6.98 (m, 2H), 5.79 (s, 2H).

A suspension of sodium (E,Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate(257 mg, 1.65 mmol) and Intermediate D-1 (150 mg, 0.55 mmol) in ethanol(2.7 mL) was stirred at 90° C. for 18 hours. The contents were dilutedwith ethyl acetate (10 mL) and water (10 mL). The mixture was treatedcarefully with HCl (1.32 mL, 1.66 mmol, 1.25M solution in ethanol).Layers were separated, and the aqueous layer was extracted withdichloromethane (3×10 mL). The organics were washed with brine (10 mL),dried over MgSO4, filtered, and the solvent was removed in vacuo.Purification by silica gel chromatography (0-20%7:1=acetonitrile:methanol in dichloromethane) provided impure compound.Purification via reverse phase HPLC provided compound I-2 (30 mg, 16%yield) as a white solid.

I-2: ¹⁻H-NMR (400 MHz, DMSO-d₆) δ 13.40-13.17 (br s, 1H), 9.14 (s, 1H),8.14 (br s, 1H), 7.57 (s, 1H), 7.52-7.45 (m, 1H), 7.40 (br s, 1H),7.29-7.19 (m, 1H), 7.13 (d, 1H), 5.81 (s, 2H).

Preparation of compound I-1

To a solution of Intermediate D-1 (50 mg, 0.55 mmol) in pyridine (2.7mL) was added a mixture of E- and Z-3-ethoxyacrylonitrile (266 mg, 2.74mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (167 mg, 1.10 mmol). Thesolution was stirred at 110° C. for 18 hours. The contents were dilutedwith ethyl acetate (10 mL), and washed with saturated ammonium chloridesolution (3 mL). Layers seperated, and aqueous layer was diluted withadditional water (10 mL). The aqueous layer was then extracted withdichloromethane (3×10 mL). Combined organic layers were washed withbrine (10 mL). The organics were dried over MgSO4, filtered, and thesolvent was removed in vacuo. Purification by silica gel chromatography(0-30% 7:1=acetonitrile:methanol in dichloromethane) provided compoundI-1 (97 mg, 54% yield) as an iridiscent pale brown solid.

Compound I-1: ¹H-NMR (400 MHz, DMSO) δ 9.13-9.07 (m, 1H), 8.12 (d, 1H),7.49-7.46 (m, 1H), 7.45 (d, 1H), 7.29-7.26 (m, 1H), 7.24-7.21 (m, 1H),6.99-6.92 (m, 3H), 6.36 (dd, 1H), 5.78 (s, 2H).

Preparation of compound I-3

Intermediate D-2 was accessed via General Procedure A in 49% yield from1-(isoxazol-3-yl)ethanone using ((3-fluorothiophen-2-yl)methyl)hydrazinehydrochloride in the second step. Intermediate D-2: ¹H-NMR (400 MHz,DMSO-d₆) δ 9.22-9.18 (m, 1H), 8.46 (br s, 3H), 7.64-7.58 (m, 1H),7.53-7.47 (m, 1H), 7.10 (t, 1H), 6.95 (d, 1H), 5.92 (s, 2H).

A suspension of sodium (E,Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate(200 mg, 0.69 mmol) and Intermediate D-2 (321 mg, 2.06 mmol) in ethanol(3.4 mL) was stirred at 90° C. for 1 hour. The contents were dilutedwith ethyl acetate (10 mL) and water (10 mL). The mixture was treatedcarefully with HCl (1.65 mL, 2.06 mmol, 1.25M solution in ethanol).Layers were separated, and the aqueous layer was extracted withdichloromethane (3×20 mL). The organics were washed with brine (10 mL),dried over MgSO4, filtered, and the solvent was removed in vacuo.Purification by silica gel chromatography (0-40%7:1=acetonitrile:methanol in dichloromethane) provided compound I-3 (86mg, 33% yield) as a white solid.

Compound I-3: ¹H-NMR (400 MHz, DMSO-d₆) δ 13.29 (br s, 1H), 9.18 (d,1H), 8.16 (br s, 1H), 7.59 (s, 1H), 7.48 (dd, 1H), 7.23 (br s, 1H), 6.95(d, 1H), 5.95 (s, 2H).

Preparation of Compound I-4

Intermediate D-3 was accessed via General Procedure A in 57% yield from1-(isoxazol-3-yl)ethanone using (thiophen-2-ylmethyl)hydrazinehydrochloride in the second step.

Intermediate D-3: ¹H-NMR (400 MHz, DMSO-d₆) δ 9.47 (d, J=8.22 Hz, 1H),9.09-9.26 (m, 1H), 7.66-7.80 (m, 1H), 7.48 (d, J=5.09 Hz, 1H), 7.29-7.42(m, 1H), 7.24 (d, J=14.48 Hz, 1H), 7.04-7.17 (m, 2H), 6.98 (t, J=4.30Hz, 1H), 5.93-6.06 (m, 1H).

A suspension of sodium (E,Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate(484 mg, 3.00 mmol) and intermediate D-3 (273 mg, 1.0 mmol) in ethanol(10 mL) was stirred at 90° C. for 18 hours. The contents were dilutedwith ethyl acetate (10 mL) and water (10 mL). The mixture was treatedcarefully with HCl (1M aqueous solution). The layers were separated, andthe aqueous layer was extracted with dichloromethane (3×10 mL). Theorganics were washed with brine (10 mL), dried over MgSO₄, filtered, andthe solvent was removed in vacuo. The residue was suspended in diethylether and filtered to give compound I-4 (190 mg, 53% yield) as anoff-white solid.

Compound I-4: ¹H-NMR (400 MHz, DMSO-d₆) δ 13.30 (br. s., 1H), 9.16 (d,J=1.17 Hz, 1H), 8.16 (br. s., 1H), 7.59 (s, 1H), 7.45 (d, J=4.70 Hz,1H), 7.24 (s, 1H), 7.14 (br. s., 1H), 6.97 (dd, J=4.70, 3.52 Hz, 1H),6.00 (s, 2H).

Preparation of Compound I-5

Intermediate D-4 was accessed via General Procedure A in 51% yield from1-(isoxazol-3-yl)ethanone using ((5-fluorothiophen-2-yl)methyl)hydrazinehydrochloride in the second step.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.25-9.20 (m, 1H), 8.81 (br s, 3H), 7.64 (s,1H), 7.10 (d, 1H), 6.82 (t, 1H), 6.60 (dd, 1H), 5.87 (s, 2H).

A suspension of sodium (E,Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate(146 mg, 0.94 mmol) and Intermediate D-4 (91 mg, 0.31 mmol) in ethanol(1.6 mL) was stirred at 90° C. for 1 hour. The contents were dilutedwith ethyl acetate (10 mL) and water (10 mL). The mixture was treatedcarefully with HCl (0.75 mL, 0.94 mmol, 1.25M solution in ethanol).Layers were separated, and the aqueous layer was extracted withdichloromethane (3×20 mL). The organics were washed with brine (10 mL),dried over MgSO4, filtered, and the solvent was removed in vacuo.Purification by silica gel chromatography (0-30%7:1=acetonitrile:methanol in dichloromethane) provided impure compound.Solids were triturated with ether (5 mL) and dried to yield compound I-5(22 mg, 18% yield) as an off-white solid. 1H-NMR (500 MHz, DMSO-d₆) δ13.28 (br s, 1H), 9.17 (d, 1H), 8.14 (br s, 1H), 7.60 (s, 1H), 7.26 (s,1H), 6.87 (br s, 1H), 6.59 (dd, 1H), 5.87 (s, 2H).

Example 2 Biological Activity Measurement by the sGC-HEK-cGMP Assay

(Assay Run with SNP Incubation)

Human embryonic kidney cells (HEK293), endogenously expressing solubleguanylate cyclase (sGC), were used to evaluate the activity of testcompounds. Compounds stimulating the sGC receptor should cause anincrease in the intracellular concentration of cGMP. HEK 293 cells wereseeded in Dulbecco's Modification of Eagle's Medium supplemented withfetal bovine serum (10% final) and L-glutamine (2 mM final) in a 200 μLvolume at a density of 1×10⁵ cells/well in a poly-D-lysine coated 96well flat bottom plate and grown overnight at 37° C. Medium wasaspirated and cells were washed with 1× Hank's Buffered Saline SaltSolution (200 μL). Cells were then incubated for 15 minutes at 37° C.with 200 μL of a 0.5 mM 3-isobutyl-1-methylxanthine (IBMX) solution.Test article and sodium nitroprusside solutions (x μM concentration fortest article solution and 10 μM concentration for SNP solution; whereinx is one of the following concentrations);

30 uM10 uM3 uM1 uM0.3 uM0.1 uM0.03 uM0.01 uM0.003 uM0.001 uM0.0003 uM0.0001 uMwere then added to the assay mixture (2 μL each) and the resultingmixture incubated at 37° C. for 10 minutes. After the 10 minuteincubation, the assay mixture was aspirated and 0.1M HCl (200 μL) wasadded to the cells. The plate was incubated at 4° C. for 30 minutes inthe 0.1M HCl to stop the reaction and lyse the cells. The plates werethen centrifuged at 1,200 g for 5 minutes at room temperature.Supernatants were collected and transferred to a new flat bottom 96 wellplate for analysis by HPLC-MS. Vehicle controls were carried out usingDMSO (1%) solutions. A known sGC stimulator, BAY 41-2272, was used asthe positive control. Samples were diluted with an equal volume of 1 MAmmonium Acetate (pH 7) to neutralize samples for better chromatography.A 2×cGMP standard solution was prepared in 0.1 M HCl and then dilutedwith an equal volume of 1 M Ammonium Acetate, with the following finalconcentrations in nM: 1024, 512, 256, 128, 64, 32, 16, 8, 4, 2, 1. cGMPconcentrations in the test plates were determined from each sample usingthe LC/MS conditions shown in Table 2 below and the calculated cGMPstandard curve. EC₅₀ values were calculated from concentration-responsecurves generated with GraphPad Prism Software.

The biological activities of some of the compounds of Formula Idetermined with the sGC-HEK assay with SNP incubation are summarized inTables 3A and 3B.

TABLE 2 (HPLC LC/MS experimental conditions) MS: Thermo Quantum orWaters LCMS Ion Mode: ESI⁺ Scan Type: MRM Dwell Collision Retention TimeEnergy Tube Time Compound: Transition (msec) (V) Lens (min) cGMP 346 >152 100 28 139 1.0 HPLC: Agilent Technologies 1200 Series with CTCAnalytics HTS PAL Column: Thermo Hypersil Gold 2.1 × 50 mm 5 micronparticle size Flow Rate: 400 uL/min Column RT Temperature: Autosampler6° C. Temperature: Injection Volume: 20 uL Mobile Phases: A = 98:2Water:Acetonitrile + 0.1% Formic Acid B = 2:98 Water:Acetonitrile + 0.1%Formic Acid Gradient: Time (min) % A % B 0 100 0 0.3 30 70 2.00 30 702.01 100 0 4 100 0

TABLE 3A Whole cell activity in the HEK assay. HEK assay HEK assay HEKassay HEK assay Emax- (Percent Emax at (Percent Emax at (Percent Emax atunconstrained Compound No. 1 μM)* 10 μM)* 30 μM)* (Percent)+ I-1 C D E EI-2 C D D D I-3 D D E D I-4 A D D E *Percent Emax was obtained at twelveconcentrations of the test compound as explained above; the results forthree of them (1, 10 and 30 μM) are shown in Table 3A. The codedefinitions for the sGC enzyme activity values, expressed as % E_(max)in the presence of 10 μM of SNP (wherein E_(max) = 100% was the activityin the HEK assay obtained with the positive control BAY 41-2272 at 10 μMin the presence of 100 μM SNP) are: A = 0 to <10% B = 10 to <20% C = 20to <40% D = 40 to <60 E = 60 or <80% F = 80 to <100% G = 100 to <120% H= 120% or higher — = not determined +The same code definitions apply forEmax unconstrained, wherein this value is defined as the maximumactivity value obtained from the full concentration-response curve forthe compound, relative to the positive control value of 100% obtained asabove. Here, the term “unconstrained” means that, during analysis of thesGC enzyme activity data, the top portion of the concentration-responsecurve was not fitted to 100%.

TABLE 3B More whole cell activity in the HEK assay. HEK assay EC50-unconstrained Compound No. (μM)# I-1 D I-2 C I-3 A I-4 E #EC₅₀ valueswere obtained from the full concentration response curve following twomethods: EC50 constrained refers to the value obtained when the top ofthe curve was fitted to 100% (wherein E_(max) = 100% was the activity inthe HEK assay obtained with the positive control BAY 41-2272 at 10 μM inthe presence of 100 μM SNP); EC₅₀ unconstrained here repored refer tothe value obtained from a full concentration-response curve when the topof the curve is not fitted to 100%. The EC50 code definitions inmicromolar (μM) are: 0.01 ≦ EC50 < 0.1 = A 0.1 ≦ EC50 < 0.5 = B 0.5 ≦EC50 < 1.0 = C 1.0 ≦ EC50 < 5.0 = D 5.0 ≦ EC50 < 10.0 = E EC50 ≧ 10.0 =F

Example 3A Biological Activity Measurements by the Purified Human sGCEnzyme Activity Assay

Human soluble guanylate cyclase enzyme (hsGC) obtained from Enzo Inc.(P/N: ALX-201-177) was used to evaluate the activity of test compounds.The assay reactions contained 0.1 M Tris (pH 8.0), 0.5 mg/mL BSA (pH8.0), 2 mM DTT, 2 mM MgCl₂, 300 μM GTP, 1 mM 3-isobutyl-1-methylxanthine(IBMX) and 5 ng human soluble guanylate cyclase enzyme. Test compoundsin DMSO were then added (2 μL, 10 or 30 μM final concentration) andincubated (water, 200 μL, 96-well plate format) at 37° C. for 30minutes. The controls were carried out using 2 μL DMSO. After the 30minute incubation, the reaction was stopped with the addition of 200 μLof cold methanol. The plate was then centrifuged at 3,200 rpm for 10minutes at room temperature. Supernatants (200 μL) were collected andtransferred to a new 96 well plate for analysis by HPLC LC/MS/MS.

An 8 point cGMP (Sigma-Aldrich P/N: G6129) standard curve was preparedin assay buffer ranging from 0.156-20 μM. Samples for the cGMP standardcurve were then diluted with an equal volume of methanol resulting infinal cGMP concentrations of 0.078-10 μM.

cGMP concentrations in all samples were determined using LC/MS/MSanalysis, using the conditions listed in Table 4 below. The cGMPstandard curve was generated using GraphPad Prism Software.

Calculations: Specific Activity was determined by the amount of cGMPformed (nmoles) per mg of sGC per min. Enzyme “fold-change” wascalculated by dividing Specific Activity for test compounds by SpecificActivity of DMSO controls.

TABLE 4 LC/MS/MS method for detection of cGMP Inlet Method: HPLC: WatersAcquity Column: Thermo Hypersile Gold PFP, 2.1 × 30 mm, 3 μm GuardColumn: Thermo Hypersile Gold, 2.1 × 10 mm Column Temp: 25° C. FlowRate: 0.4 mL/min Auto sampler: Acquity; 6° C. Injection Volume: 10 μLMobile Phases: A = 0.1% Acetic Acid (v/v) in 100% water B = 0.1% AceticAcid (v/v) in 100 methanol Gradient: Time (min) % A % B Curve 0 95  5 60.5 95  5 6 0.6 10 90 6 2.0 10 90 6 2.1 95  5 6 4 (end) MS File:cGMP.exp Mass Spectrum: Waters Quattro micro Ionization: ES ⁺ Source,Desolvation: 150° C., 450° C. MS Function: MRM Dwell Cone CollisionCompound Transition (sec) (V) Energy (eV) cGMP 346 > 152 0.1 35 20

Example 3B Biological Measurement by the Purified Human sGC EnzymeSynergy Performed in the Presence of Sodium Nitroprusside (SNP), aNitric Oxide Donor

Enzyme assays were performed as described above, but the assay was donein the presence of 1 μM sodium nitroprusside (SNP). Data for compoundsof Table 1 is summarized in Table 5 below.

TABLE 5 Enzyme Data With SNP.* Enzyme Activity (increase at 30 CompoundNo. μM with SNP)* I-1 D I-2 D *The compounds were tested at aconcentration of 30 μM in the presence of 1 μM SNP. The code for thefold increase in enzyme activity is: A = no increase to <2 fold increaseB = 2 to <5 fold increase C = 5 to <10 fold increase D = 10 or <20 foldincrease E = 20 to 30 fold increase F = >30 fold increase

Example 4 Biological Activity Measurement by the Thoracic Aortic RingsAssay

Thoracic aortic rings were dissected from anesthetized (isoflurane) maleSprague-Dawley rats weighing 275-299 g. Tissues were immediatelytransferred to ice-cold Krebs-Henseleit solution, which had been aeratedwith 95% 02 and 5% CO₂ for 30 minutes. Following removal of connectivetissue, aortic sections were cut into 4 rings (˜2 mm each) and suspendedon 2 L-shaped hooks, with one hook fixed at the bottom of the tissuebath (Schuler Organ Bath, Harvard Apparatus) and the other connected toa force transducer (F30 Force Transducer, Harvard Apparatus). Bathscontained Krebs Henseleit solution (10 mL) heated to 37° C. and aeratedwith 95% O₂ and 5% CO₂. Rings were brought to an initial tension of0.3-0.5 g and gradually raised to a resting tension of 1.0 g over 60minutes. Rings were rinsed with Krebs Henseleit solution (heated to 37°C. and aerated with 95% 02 and 5% CO₂) at 15 minute intervals until astable baseline was obtained. Rings were considered to be stable after aresting tension of 1.0 g was maintained (for approximately 10 minutes)without need for adjustment. Rings were then contracted with 100 ng/mLphenylephrine by adding 100 uL of a 10 μg/mL phenylephrine stocksolution. Tissues achieving a stable contraction were then treated in acumulative, dose dependent manner with test compounds prepared indimethylsulfoxide (DMSO). In some cases, tissues were rinsed three timesover a 5 minute period with Krebs-Heinseleit's solution (heated to 37°C. and aerated with 95% 02 and 5% CO₂), allowed to stabilize atbaseline, and then used for characterization of other test articles orDMSO effects. All data were collected using the HSE-ACAD softwareprovided by Harvard Apparatus. Percent relaxation effects werecalculated in Microsoft Excel using the recorded tension value of 100ng/mL phenylephrine treatment as 0% inhibition and treatment with 100 μM3-isobutyl-1-methylxanthine as 100% inhibition. EC₅₀ values werecalculated from concentration-response curves generated with GraphPadPrism Software.

Example 5 Biological Activity Measurement by the Thoracic Aortic RingsAssay

As an alternative thoracic aortic rings assay, the procedure of Example5 was used except that percent relaxation effects were calculated inMicrosoft Excel using the recorded tension value of 100 ng/mLphenylephrine treatment as 0% inhibition and, after washing the tissuewith buffer, the original resting tension of the tissue was used as 100%inhibition.

A number of embodiments have been described. Nevertheless, it will beunderstood that various modifications may be made without departing fromthe spirit and scope of the invention.

Example 6 Animal Models Descriptions Lamb Model of PulmonaryHemodynamics Using Inhaled sGC Stimulator

(“Inhaled Agonists of Soluble Guanylate Cyclase Induce SelectivePulmonary Vasodilation”, Oleg V. et al, American J of Resp and CriticalCare Medicine, Vol 176, 2007, p 1138)

It is possible to test whether inhalation of novel dry-powdermicroparticle formulations containing sGC stimulators would produceselective pulmonary vasodilation in lambs with acute pulmonaryhypertension by following a published procedure. It is also possible toevaluate the combined administration of the microparticles of sGCstimulator and inhaled nitric oxide (iNO) in this system. Finally, it ispossible to examine whether inhaling microparticles of an sGC stimulatorwould produce pulmonary vasodilation when the response to iNO (induciblenitric oxide synthase) is impaired.

Protocol: In awake, spontaneously breathing lambs instrumented withvascular catheters and a tracheostomy tube, U-46619 is infusedintravenously to increase mean pulmonary arterial pressure to 35 mm Hg.Inhalation of microparticles composed of either BAY 41-2272, BAY41-8543, or BAY 58-2667 and excipients (dipalmitoylphosphatidylcholine,albumin, lactose) produced dose dependent pulmonary vasodilation andincreased transpulmonary cGMP release without significant effect on meanarterial pressure. Inhalation of microparticles containing BAY 41-8543or BAY 58-2667 increased systemic arterial oxygenation. The magnitudeand duration of pulmonary vasodilation induced by iNO were augmentedafter inhaling BAY 41-8543 microparticles. Intravenous administration of1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes theprosthetic heme group of sGC, markedly reduced the pulmonary vasodilatoreffect of iNO. In contrast, pulmonary vasodilation and transpulmonarycGMP release induced by inhaling BAY 58-2667 microparticles were greatlyenhanced after treatment with ODQ. Thus, inhalation of microparticlescontaining agonists of sGC may provide an effective novel treatment forpatients with pulmonary hypertension, particularly when responsivenessto iNO is impaired by oxidation of sGC. Note: BAY 41-2272, BAY 41-8543are sGC stimulators whereas BAY 58-2667 is an sGC activator.

Electrical Field Stimulated Guinea Pig Tracheal Smooth Muscle In Vitro(Ex Vivo) Model for the Assessment of Bronchodilation.

It is possible to assess the bronchodilating effects of sGC stimulatorsby using the system described below. This system allowed us to determinepotency, efficacy and duration of action of several sGC stimulators, aswell as to assess potential side effects such as blood pressure, orheart rate changes.

Animals: Guinea pig, Dunkin Hartley, male, Full barrier-bred andcertified free of specific micro-organisms on receipt 525-609 g on theexperimental day, Harlan UK Ltd. Guinea pigs were housed in a group of 4in solid-bottomed cages with Gold Flake bedding in a controlledenvironment (airflow, temperature and humidity). Food (FD1, Special DietServices) and water were provided ad libitum.

Guinea Pig Tracheal Smooth Muscle Contraction in Response to EFS.Assessment of Compound Potency and Efficacy:

On each experimental day, a guinea pig was killed by exposure to arising concentration of CO2 and the trachea removed. The trachea wascleaned of extraneous tissue and cut open longitudinally in a lineopposite the muscle, opened out and cut into strips 2-3 cartilage ringswide. A cotton loop was attached to one end of each tracheal strip and alength of cotton to the other end. Tracheal strips were then suspendedbetween two platinum electrodes, using tissue holders, in a Myobathsystem (World Precision Instruments Stevenage, UK). The loop wasattached over the hook at the bottom of the tissue holder and the otherend attached to the arm of a FORT10 force transducer (World PrecisionInstruments Stevenage, UK) ensuring that the tissue was positionedbetween the two platinum electrodes. The whole assembly was then loweredinto a 10 ml tissue bath containing modified Kreb's-Henseleit buffer, at37° C., bubbled with Carbogen. A 1 g tension was applied to each pieceof tissue and the tissue washed, followed by a 1 hour stabilizationperiod. Once the tissues had been allowed to stabilize, the apparatusfor electrical field stimulation was set to deliver a stimulation offrequency 80 Hz pulse width 0.1 ms, with a gated, uni-polar pulse, every2 minutes using a DS8000 8 channel digital stimulator (World PrecisionInstruments Stevenage, UK). A voltage response curve was carried out oneach tracheal strip at 2, 4, 6, 7, 8, 10, 12 V and a sub-maximal voltagethen selected to apply to each tissue during the remainder of theexperiment. Guinea pig tracheal smooth muscle (GPTSM) contraction wasinduced using sub-maximal Electrical Field Stimulation (EFS) (It is alsopossible to induce contraction by using a spasmogen substance, such asmethacholine or histamine as described in Coleman et al.*). Compoundswere dissolved in 100% DMSO at 3×10-2M and aliquots stored at −200 C. Aseparate aliquot was used for each experiment. Tissues were washed withKreb's buffer and stimulated using the previously determined sub-maximalvoltage for 1 hour to establish a stable baseline contraction prior toassessment of compound activity. *“Novel and Versatile SuperfusionSystem. Its use in the Evaluation of Some Spasmogenic and SpasmolyticAgents Using Guinea pig isolated Tracheal Smooth Muscle.”, R. A. Colemanet al., J. Pharmacol. Methods, 21, 71-86, 1989.

A cumulative dose response curve (DRC) to each test substance was thenperformed and changes in smooth muscle contraction measured. The effectof each test substance in each experiment was expressed as a percentageinhibition of the baseline contraction, normalized to the relevantvehicle controls. The experiment was performed three times, using tissuefrom three different animals. The data from all three experiments waspooled, the DRC plotted, and the test substance potency and efficacydetermined. The potency of Ipratropium bromide was assessed alongsidethe test compounds and the IC50 determined to be 0.86 nM (95% Cl,0.78-0.94), in agreement with data previously produced in the system.

1-63. (canceled)
 64. A method of treating a disease, health condition ordisorder in a subject, comprising administering a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, to the subject in need of the treatment,

wherein: ring B is a 5-membered heteroaryl ring selected from furan orthiophene; n is an integer selected from 0 to 3; each J^(B) isindependently selected from halogen, —CN, a C₁₋₆ aliphatic, —OR^(B) or aC₃₋₈ cycloaliphatic group; wherein each said C₁₋₆ aliphatic and eachsaid C₃₋₈ cycloaliphatic group is optionally and independentlysubstituted with up to 3 instances of R³; each R^(B) is independentlyselected from hydrogen, a C₁₋₆ aliphatic or a C₃₋₈ cycloaliphatic ring;wherein each said C₁₋₆ aliphatic and each said C₃₋₈ cycloaliphatic ringis optionally and independently substituted with up to 3 instances ofR^(3a); each R³ is independently selected from halogen, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); each R^(3a) isindependently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); X is selected from N, C-J^(D) orC—H; o is an integer selected from 0 to 3; each J^(D) is independentlyselected from halogen, —NO₂, —OR^(D), —SR^(D), —C(O)R^(D), —C(O)OR^(D),—C(O)N(R^(D))₂, —CN, —N(R^(D))₂, —N(R^(d))C(O)R^(D),—N(R^(d))C(O)OR^(D), —SO₂R^(D), —SO₂N(R^(D))₂, —N(R^(d))SO₂R^(D), a C₁₋₆aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈ cycloaliphatic ring, a 6 to10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5 to10-membered heteroaryl ring; wherein each said 4 to 8-memberedheterocylic ring and each said 5 to 10-membered heteroaryl ring containsbetween 1 and 3 heteroatoms independently selected from O, N or S; andwherein each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring,each said 6 to 10-membered aryl ring, each said 4 to 8-memberedheterocyclic ring and each said 5 to 10-membered heteroaryl ring isoptionally and independently substituted with up to 3 instances of R⁵;each R^(D) is independently selected from hydrogen, a C₁₋₆ aliphatic,—(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 8-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said 4 to 8-membered heterocylic ring and each said 5 to 6-memberedheteroaryl ring contains between 1 and 3 heteroatoms independentlyselected from O, N or S; and wherein each said C₁₋₆ aliphatic, each saidC₃₋₈ cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,each said phenyl and each said 5 to 6-membered heteroaryl ring isoptionally and independently substituted with up to 3 instances ofR^(5a); each R^(d) is independently selected from hydrogen, a C₁₋₆aliphatic, —(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to8-membered heterocyclic ring, phenyl or a 5 to 6-membered heteroarylring; wherein each said heterocylic ring and each said heteroaryl ringcontains between 1 and 3 heteroatoms independently selected from O, N orS; and wherein each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphaticring, each said 4 to 8-membered heterocyclic ring, each said phenyl andeach said 5 to 6-membered heteroaryl ring is optionally andindependently substituted by up to 3 instances of R^(5b); each R^(f) isindependently selected from a C₃₋₈ cycloaliphatic ring, a 4 to8-membered heterocyclic ring, phenyl or a 5 to 6-membered heteroarylring; wherein each said heterocylic ring and each said heteroaryl ringcontains between 1 and 3 heteroatoms independently selected from 0, N orS; and wherein each said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphaticring, each said 4 to 8-membered heterocyclic ring, each said phenyl andeach said 5 to 6-membered heteroaryl ring is optionally andindependently substituted by up to 3 instances of R^(5c); when J^(D) is—C(O)N(R^(D))₂, —N(R^(D))₂ or —SO₂N(R^(D))₂, the two instances of R^(D)together with the nitrogen atom attached to the R^(D), alternativelyform a 4 to 8-membered heterocyclic ring or a 5-membered heteroarylring; wherein each said 4 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally contains up to 2 additionalheteroatoms independently selected from N, O or S, and wherein each said4 to 8-membered heterocyclic ring and each said 5-membered heteroarylring is optionally and independently substituted by up to 3 instances ofR⁵; or when J^(D) is —N(R^(d))C(O)R^(D), the R^(D) group together withthe carbon atom attached to the R^(D) group, with the nitrogen atomattached to the R^(d) group and with the R^(d) group alternatively forma 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;wherein each said 4 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally contains up to 2 additionalheteroatoms independently selected from N, O or S, and wherein each said4 to 8-membered heterocyclic ring and each said 5-membered heteroarylring is optionally and independently substituted by up to 3 instances ofR⁵; when J^(D) is —N(R^(d))C(O)OR^(D), the R^(D) group together with theoxygen atom attached to the R^(D) group, with the carbon atom of the—C(O)— portion of the —N(R^(d))C(O)OR^(D) group, with the nitrogen atomattached to the R^(d) group, and with the R^(d) group alternatively forma 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;wherein each said 4 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally contains up to 2 additionalheteroatoms independently selected from N, O or S, and wherein each said4 to 8-membered heterocyclic ring and each said 5-membered heteroarylring is optionally and independently substituted by up to 3 instances ofR⁵; when J^(D) is —N(R^(d))SO₂R^(D), the R^(D) group together with theoxygen atom attached to the R^(D) group, with the sulfur atom attachedto said oxygen atom in the —SO₂R^(D) portion of the N(R^(d))SO₂R^(D)group, with the nitrogen atom attached to the R^(d) group, and with theR^(d) group alternatively form a 4 to 8-membered heterocyclic ring or a5-membered heteroaryl ring; wherein each said 4 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallycontains up to 2 additional heteroatoms independently selected from N, Oor S, and wherein each said 4 to 8-membered heterocyclic ring and eachsaid 5-membered heteroaryl ring is optionally and independentlysubstituted by up to 3 instances of R⁵; each R⁵ is independentlyselected from halogen, —CN, —NO₂, C₁₋₄ alkyl, a C₇₋₁₂ aralkyl, C₃₋₈cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶,—COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂,—N(R⁶)SO₂R⁶, phenyl or an oxo group; wherein each said phenyl group isoptionally and independently substituted with up to 3 instances ofhalogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and whereineach said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen; each R^(5a)is independently selected from halogen, —CN, —NO₂, C₁₋₄ alkyl, a C₇₋₁₂aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, —OR⁶,—SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁶)C(O)R⁶, —N(R⁶)₂,—SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an oxo group; wherein eachsaid phenyl group is optionally and independently substituted with up to3 instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,—NO₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄haloalkyl); and wherein each said C₇₋₁₂ aralkyl and each said cycloalkylgroup is optionally and independently substituted with up to 3 instancesof halogen; each R^(5b) is independently selected from halogen, —CN,—NO₂, C₁₋₄ alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ haloalkyl,C₁₋₄ cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,—N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, phenyl or an oxogroup; wherein each said phenyl group is optionally and independentlysubstituted with up to 3 instances of halogen, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄alkyl) or —O(C₁₋₄ haloalkyl); and wherein each said C₇₋₁₂ aralkyl andeach said cycloalkyl group is optionally and independently substitutedwith up to 3 instances of halogen; each R^(5c) is independently selectedfrom halogen, —CN, —NO₂, C₁₋₄ alkyl, a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkylring, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, —OR⁶, —SR⁶, —OCOR⁶, —COR⁶,—C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂,—N(R⁶)SO₂R⁶, phenyl or an oxo group; wherein each said phenyl group isoptionally and independently substituted with up to 3 instances ofhalogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and whereineach said C₇₋₁₂ aralkyl and each said cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen; each R⁶ isindependently selected from hydrogen, a C₁₋₄ alkyl, a C₂₋₄ alkenyl,phenyl, a C₇₋₁₂ aralkyl or a C₃₋₈ cycloalkyl ring; wherein each saidC₁₋₄ alkyl, each said C₂₋₄ alkenyl, each said phenyl, each said C₇₋₁₂aralkyl and each said C₃₋₈ cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen;alternatively, two instances of R⁶ linked to the same nitrogen atom ofR⁵, together with said nitrogen atom of R⁵, form a 5 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 5to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally contains up to 2 additional heteroatoms independentlyselected from N, O or S; or alternatively, one instance of R⁶ linked toa nitrogen atom of R⁵ and one instance of R⁶ linked to a carbon orsulfur atom of the same R⁵, together with said nitrogen and said carbonor sulfur atom of the same R⁵, form a 5 to 8-membered heterocyclic ringor a 5-membered heteroaryl ring; wherein each said 5 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallycontains up to 2 additional heteroatoms independently selected from N, Oor S; or, alternatively, two J^(D) groups attached to two vicinal ring Datoms, taken together with said two vicinal ring D atoms, form a 5 to7-membered heterocycle resulting in a fused ring D wherein said 5 to7-membered heterocycle contains from 1 to 3 heteroatoms independentlyselected from N, O or S; and wherein said 5 to 7-membered heterocycle isoptionally and independently substituted by up to 3 instances ofhalogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl), oxo or phenyl;wherein said phenyl is optionally and independently substituted by up tothree instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,—NO₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄haloalkyl); R^(C) is a ring C; ring C is a phenyl ring, a monocyclic 5or 6-membered heteroaryl ring, a bicyclic 8 to 10-membered heteroarylring, a monocyclic 3 to 10-membered cycloaliphatic ring, or a monocyclic4 to 10-membered heterocycle; wherein said monocyclic 5 or 6-memberedheteroaryl ring, said bicyclic 8 to 10-membered heteroaryl ring, or saidmonocyclic 4 to 10-membered heterocycle contain between 1 and 4heteroatoms selected from N, O or S; wherein said monocyclic 5 or6-membered heteroaryl ring is not a 1,3,5-triazinyl ring; and whereinsaid phenyl, monocyclic 5 to 6-membered heteroaryl ring, bicyclic 8 to10-membered heteroaryl ring, or monocyclic 4 to 10-membered heterocycleis optionally and independently substituted with up to 3 instances off;each J^(C) is independently selected from halogen, —CN, —NO₂, a C₁₋₆aliphatic, —OR″, —SR^(H), —N(R^(H))₂, a C₃₋₈ cycloaliphatic ring or a 4to 8-membered heterocyclic ring; wherein said 4 to 8-memberedheterocyclic ring contains 1 or 2 heteroatoms independently selectedfrom N, O or S; wherein each said C₁₋₆ aliphatic, each said C₃₋₈cycloaliphatic ring and each said 4 to 8-membered heterocyclic ring, isoptionally and independently substituted with up to 3 instances of R⁷;or alternatively, two J^(C) groups attached to two vicinal ring C atoms,taken together with said two vicinal ring C atoms, form a 5 to7-membered heterocycle resulting in a fused ring C; wherein said 5 to7-membered heterocycle contains from 1 to 2 heteroatoms independentlyselected from N, O or S; each R^(H) is independently selected fromhydrogen, a C₁₋₆ aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to8-membered heterocyclic ring; wherein each said 4 to 8-memberedheterocylic ring contains between 1 and 3 heteroatoms independentlyselected from O, N or S; and wherein each said C₁₋₆ aliphatic, each saidC₃₋₈ cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring,is optionally and independently substituted with up to 3 instances ofR^(7a); alternatively, two instances of R^(H) linked to the samenitrogen atom of J^(C), together with said nitrogen atom of J^(C), forma 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;wherein each said 4 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally contains up to 2 additionalheteroatoms independently selected from N, O or S, and wherein each said4 to 8-membered heterocyclic ring and each said 5-membered heteroarylring is optionally and independently substituted by up to 3 instances ofR^(7b); or each R⁷ is independently selected from halogen, —CN, —NO₂,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂,or an oxo group; wherein each said cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen; each R^(7a)is independently selected from halogen, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or an oxo group;wherein each said cycloalkyl group is optionally and independentlysubstituted with up to 3 instances of halogen; each R^(7b) isindependently selected from halogen, —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₈ cycloalkyl ring, —OR⁸, —SR⁸, —N(R⁸)₂, or an oxo group;wherein each said cycloalkyl group is optionally and independentlysubstituted with up to 3 instances of halogen; each R⁸ is independentlyselected from hydrogen, a C₁₋₄ alkyl, C₁₋₄ haloalkyl or a C₃₋₈cycloalkyl ring; wherein each said cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen;alternatively, two instances of R⁸ linked to the same nitrogen atom ofR⁷, together with said nitrogen atom of R⁷, form a 5 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 5to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally contains up to 2 additional heteroatoms independentlyselected from N, O or S; and R^(A) is selected from hydrogen, halogen,C₁₋₄ alkyl or C₁₋₄ haloalkyl; wherein the disease, health condition ordisorder is (a) a peripheral or cardiac vascular disorder or healthcondition selected from: pulmonary hypertension, pulmonary arterialhypertension, and associated pulmonary vascular remodeling, localizedpulmonary thrombosis, right heart hypertrophy, pulmonary hypertonia,primary pulmonary hypertension, secondary pulmonary hypertension,familial pulmonary hypertension, sporadic pulmonary hypertension,pre-capillary pulmonary hypertension, idiopathic pulmonary hypertension,thrombotic pulmonary artheriopathy, plexogenic pulmonary artheriopathy;pulmonary hypertension associated with or related to: left ventriculardysfunction, hypoxemia, mitral valve disease, constrictive pericarditis,aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonaryfibrosis, anomalous pulmonary venous drainage, pulmonary venooclusivedisease, pulmonary vasculitis, collagen vascular disease, congenitalheart disease, pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, apnea, alveolar hypoventilation disorders,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorders, chronic thromboembolism, pulmonary embolism, connectivetissue disease, lupus, schitosomiasis, sarcoidosis, chronic obstructivepulmonary disease, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis and compressedpulmonary vessels; (b) a health disorder related to high blood pressureand decreased coronary blood flow selected from: increased acute andchronic coronary blood pressure, arterial hypertension, vasculardisorder resulting from heart disease, stroke, cerebral ischemia, orrenal failure, congestive heart failure, thromboembolic disorders,ischemias, myocardial infarction, stroke, transient ischemic attacks,stable or unstable angina pectoris, arrhythmias, diastolic dysfunction,coronary insufficiency; (c) atherosclerosis, restenosis, percutaneoustransluminal coronary angioplasties or inflammation; (d) livercirrhosis, hepatic fibrosis, hepatic stellate cell activation, hepaticfibrous collagen and total collagen accumulation, liver disease ofnecro-inflammatory and/or of immunological origin; or (e) a urogenitalsystem disorder selected from renal fibrosis, renal failure resultingfrom chronic kidney diseases or insufficiency, prostate hypertrophy,erectile dysfunction, female sexual dysfunction and incontinence. 65.The method of claim 64, wherein the disease, health condition ordisorder is (a) a peripheral or cardiac vascular disorder or healthcondition selected from: pulmonary hypertension, pulmonary arterialhypertension, and associated pulmonary vascular remodeling, localizedpulmonary thrombosis, right heart hypertrophy, pulmonary hypertonia,primary pulmonary hypertension, secondary pulmonary hypertension,familial pulmonary hypertension, sporadic pulmonary hypertension,pre-capillary pulmonary hypertension, idiopathic pulmonary hypertension,thrombotic pulmonary artheriopathy, plexogenic pulmonary artheriopathy;pulmonary hypertension associated with or related to: left ventriculardysfunction, hypoxemia, mitral valve disease, constrictive pericarditis,aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonaryfibrosis, anomalous pulmonary venous drainage, pulmonary venooclusivedisease, pulmonary vasculitis, collagen vascular disease, congenitalheart disease, pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, apnea, alveolar hypoventilation disorders,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorders, chronic thromboembolism, pulmonary embolism, connectivetissue disease, lupus, schitosomiasis, sarcoidosis, chronic obstructivepulmonary disease, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis or compressedpulmonary vessels; (b) liver cirrhosis, or (c) a urogenital systemdisorder selected from renal fibrosis, renal failure resulting fromchronic kidney diseases or insufficiency, erectile dysfunction or femalesexual dysfunction.
 66. The method of claim 65, wherein the disease,health condition or disorder is pulmonary hypertension, pulmonaryarterial hypertension, and associated pulmonary vascular remodeling,localized pulmonary thrombosis, right heart hypertrophy, pulmonaryhypertonia, primary pulmonary hypertension, secondary pulmonaryhypertension, familial pulmonary hypertension, sporadic pulmonaryhypertension, pre-capillary pulmonary hypertension, idiopathic pulmonaryhypertension, thrombotic pulmonary arteriopathy, plexogenic pulmonaryarteriopathy or chronic obstructive pulmonary disease, liver cirrhosis,renal fibrosis, renal failure resulting from chronic kidney diseases orinsufficiency, erectile dysfunction or female sexual dysfunction. 67.The method of claim 66, wherein the disease, health condition ordisorder is pulmonary hypertension, pulmonary arterial hypertension, andassociated pulmonary vascular remodeling, pulmonary hypertonia, primarypulmonary hypertension, secondary pulmonary hypertension, familialpulmonary hypertension, sporadic pulmonary hypertension, pre-capillarypulmonary hypertension or idiopathic pulmonary hypertension.
 68. Themethod of claim 64, further comprising administering an effective amountof one or more additional therapeutic agents to the subject.
 69. Themethod of claim 68, wherein the one or more additional therapeuticagents are selected from endothelium-derived releasing factor, NOdonors, substances that enhance cGMP concentrations, nitric oxidesynthase substrates, compounds which enhance eNOS transcription,NO-independent heme-independent sGC activators, heme-dependent sGCstimulators; inhibitors of cGMP degradation, calcium channel blockers,endothelin receptor antagonists, prostacyclin derivatives,antihyperlipidemics, anticoagulants, antiplatelet drugs, ACE inhibitors,supplemental oxygen, beta blockers, antiarrhythmic agents, diuretics,exogenous vasodilators, bronchodilators, corticosteroids, dietarysupplements, PGD2 receptor antagonists, immunosuppressants,non-steroidal antiasthmatics, non-steroidal anti-inflammatory agents,cyclooxygenase-2 inhibitors or anti-diabetic agents.
 70. (canceled) 71.The method of claim 65, further comprising administering an effectiveamount of one or more additional therapeutic agents to the subject. 72.The method of claim 71, wherein the one or more additional therapeuticagents are selected from endothelium-derived releasing factor, NOdonors, substances that enhance cGMP concentrations, nitric oxidesynthase substrates, compounds which enhance eNOS transcription,NO-independent heme-independent sGC activators, heme-dependent sGCstimulators; inhibitors of cGMP degradation, calcium channel blockers,endothelin receptor antagonists, prostacyclin derivatives,antihyperlipidemics, anticoagulants, antiplatelet drugs, ACE inhibitors,supplemental oxygen, beta blockers, antiarrhythmic agents, diuretics,exogenous vasodilators, bronchodilators, corticosteroids, dietarysupplements, PGD2 receptor antagonists, immunosuppressants,non-steroidal antiasthmatics, non-steroidal anti-inflammatory agents,cyclooxygenase-2 inhibitors or anti-diabetic agents.
 73. The method ofclaim 66, further comprising administering an effective amount of one ormore additional therapeutic agents to the subject.
 74. The method ofclaim 73, wherein the one or more additional therapeutic agents areselected from endothelium-derived releasing factor, NO donors,substances that enhance cGMP concentrations, nitric oxide synthasesubstrates, compounds which enhance eNOS transcription, NO-independentheme-independent sGC activators, heme-dependent sGC stimulators;inhibitors of cGMP degradation, calcium channel blockers, endothelinreceptor antagonists, prostacyclin derivatives, antihyperlipidemics,anticoagulants, antiplatelet drugs, ACE inhibitors, supplemental oxygen,beta blockers, antiarrhythmic agents, diuretics, exogenous vasodilators,bronchodilators, corticosteroids, dietary supplements, PGD2 receptorantagonists, immunosuppressants, non-steroidal antiasthmatics,non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors oranti-diabetic agents.